Tricyclic Tetrahydroquinoline derivatives and tricyclic tetrahydroquinoline combinatorial libraries

ABSTRACT

The present invention relates to novel tricyclic tetrahydroquinoline compounds of the following formula, libraries containing such compounds, and to the generation of such combinatorial libraries composed of such compounds: ##STR1## wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n, and Y have the meanings provided.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to the synthesis of heterocycliccompounds based on the tricyclic tetrahydroquinoline ring. Morespecifically, the invention provides novel tricyclictetrahydroquinolines as well as novel libraries comprised of suchcompounds.

2. Background Information

The process of discovering new therapeutically active compounds for agiven indication involves the screening of all compounds from availablecompound collections. From the compounds tested one or more structure(s)is selected as a promising lead. A large number of related analogs arethen synthesized in order to develop a structure-activity relationshipand select one or more optimal compounds. With traditional one-at-a-timesynthesis and biological testing of analogs, this optimization processis long and labor intensive. Adding significant numbers of newstructures to the compound collections used in the initial screeningstep of the discovery and optimization process cannot be accomplishedwith traditional one-at-a-time synthesis methods, except over a timeframe of months or even years. Faster methods are needed that allow forthe preparation of up to thousands of related compounds in a matter ofdays or a few weeks. This need is particularly evident when it comes tosynthesizing more complex compounds, such as tricyclictetrahydroquinolines.

Solid-phase techniques for the synthesis of peptides have beenextensively developed and combinatorial libraries of peptides have beengenerated with great success. During the past four years there has beensubstantial development of chemically synthesized combinatoriallibraries (SCLs) made up of peptides. The preparation and use ofsynthetic peptide combinatorial libraries has been described, forexample, by Dooley in U.S. Pat. No. 5,367,053, Huebner in U.S. Pat. No.5,182,366, Appel et al. in WO PCT 92/09300, Geysen in published EuropeanPatent Application 0 138 855 and Pirrung in U.S. Pat. No. 5,143,854.Such SCLs provide the efficient synthesis of an extraordinary number ofvarious peptides in such libraries and the rapid screening of thelibrary which identifies lead pharmaceutical peptides.

Combinatorial approaches have recently been extended to "organic" ornon-peptide, libraries. The organic libraries to the present, however,are of limited diversity and generally relate to peptidomimeticcompounds; in other words, organic molecules that reta in peptide chainpharmacophore groups similar to those present in the correspondingpeptide.

Combinatorial chemical methods have bee n applied to a limited number ofheterocyclic compounds, as described, for example, in U.S. Pat. No.5,288,514 to Ellman, U.S. Pat. No. 5,324,483 to Cody et al. and Goff andZuckermann, J. Org. Chem., 60:5748-5749 (1995). Additionally, there isU.S. Pat. No. 5,549,974 to Holmes and U.S. Pat. No. 5,506,337 toSummerton and Weller. However, the heterocyclic libraries to d at econtain compounds of limited diversity and complexity.

Five 3,4-cyclopentenyl substituted tetrahydroquinolines have Grieco andBahsas, Tetrahedron Letters, 29:5855-5858 (1988). However, theirprocedures are limited to use of one equivalent of aldehyde forformation of the imine intermediate in order to limit the heteroDiel-Alder reaction with cyclopentadiene and thus avoid a double heteroDiels-Alder reaction. Gregoire et al., Tetrahedron Letters, 32:7099(1991), has also described classical synthesis of the cyclopentadienehetero Diels-Alder reaction to prepare a series of nine aza-steroidderivatives. There remains a need, however, to prepare these compoundsin libraries of substantial molecular diversity.

Patent application WO 94/08051 discloses the reaction of ether-linkedaldehyde-derived imines with dihydrofuran under Lewis acid catalysis.

However, the library described therein was limited to 108 compounds.

Moreover, while lanthanide triflates have been reported to effect thepreparation of tricyclic tetrahydroquinolines they are expensive and thereaction scope where they have been employed is very limited. See forexample, Kobayashi et al., Chemistry Letters, 423 (1995).

Substituent limitations have been overcome for mixtures of peptides andpeptidomimetics through the use of solid phase techniques versussolution-phase. An important step in the development of solid-phasetechniques was the discovery of methods to identify active individualcompounds from soluble mixtures of large numbers of compounds, asdescribed, for example, by Rutter in U.S. Pat. No. 5,010,175 and Simonin WO PCT 91/19735. These soluble mixture methods, however, have rarelybeen applied to the syntheses of complex heterocyclic structures. Thereexists a need to develop more complex "organic" libraries based onheterocyclic medicinal compounds which would require less time andeffort in the synthesis and testing needed to bring an organicpharmaceutical product to fruition. In short, improved methods forgenerating therapeutically useful heterocyclic compounds, such astricyclic tetrahydroquinoline derivatives, are desired.

This invention satisfies these needs and provides related advantages aswell. The present invention overcomes the known limitations to classicalorganic synthesis of tricyclic tetrahydroquinolines and as well as theshortcomings of combinatorial chemistry with heterocycles. The presentinvention combines the techniques of solid-phase synthesis ofheterocycles and the general techniques of synthesis of combinatoriallibraries to prepare new tricyclic tetrahydroquinoline compounds.

SUMMARY OF THE INVENTION

The present invention relates to novel tricyclic tetrahydroquinolinecompounds of the following formula, libraries containing at least two ormore such compounds, and to the generation of such combinatoriallibraries composed of such compounds: ##STR2## wherein R¹, R², R³, R⁴,R⁵, R⁶, n and Y have the meanings provided below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides Reaction Scheme I for preparing the tricyclictetrahydroquinoline compounds of the present invention.

FIG. 2 shows a more detailed reaction scheme, Reaction Scheme II, forthe preparation of the subject tricyclic tetrahydroquinolines andlibraries containing the same.

FIG. 3 provides Reaction Scheme III for the preparation of libraries andcompounds containing alternatively branched tricyclictetrahydroquinolines at the R⁸ position.

FIG. 4 provides Reaction Scheme IV for the preparation of libraries andcompounds containing alternatively substituted tricyclictetrahydroquinolines at the R⁶ position.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel derivatives and libraries of novelderivatives of variously substituted tricyclic tetrahydroquinolinecompounds of Formula I: ##STR3##

In the above Formula I:

R¹ is absent or present and, when present, is C₁ to C₁₀ alkylene, C₁ toC₁₀ substituted alkylene, C₂ to C₁₀ alkenyl, C₂ to C₁₀ substitutedalkenyl, C₂ to C₁₀ alkynyl, C₂ to C₁₀ substituted alkynyl, C₃ to C₇cycloalkyl, C₃ to C₇ substituted cycloalkyl, C₅ to C₇ cycloalkenyl, C₅to C₇ substituted cycloalkenyl, phenylene, substituted phenylene,naphthyl, substituted naphthyl, C₇ to C₁₂ phenylalkyl, C₇ to C₁₂substituted phenylalkyl, heterocyclic ring, substituted heterocyclicring, heteroaryl ring, substituted heteroaryl ring, amino,(monosubstituted)amino, a group of the formula: --CH₂ C(O)NH-- or agroup of the formula:

    --(CH.sub.2).sub.p --Ar--(CH.sub.2).sub.q --

wherein p and q are independently selected from a number 0 to 6, whereinboth are not 0; and Ar is an aryl group selected from the groupconsisting of phenyl, substituted phenyl, heteroaryl ring or substitutedheteroaryl ring,

R², R³, and R⁴ are, independently, a hydrogen atom, halo, hydroxy,protected hydroxy, cyano, nitro, C₁ to C₁₀ alkyl, C₂ to C₁₀ alkenyl, C₂to C₁₀ alkynyl, C₁ to C₁₀ substituted alkyl, C₂ to C₁₀ substitutedalkenyl, C₂ to C₁₀ substituted alkynyl, C₁ to C₇ alkoxy, C₁ to C₇substituted alkoxy, C₁ to C₇ acyloxy, C₁ to C₇ acyl, C₃ to C₇cycloalkyl, C₃ to C₇ substituted cycloalkyl, C₅ to C₇ cycloalkenyl, C₅to C₇ substituted cycloalkenyl, heterocyclic ring, substitutedheterocyclic ring, C₇ to C₁₂ phenylalkyl, C₇ to C₁₂ substitutedphenylalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl,cyclic C₂ to C₇ alkylene, substituted cyclic C₂ to C₇ alkylene, cyclicC₂ to C₇ heteroalkylene, substituted cyclic C₂ to C₇ heteroalkylene,carboxy, protected carboxy, hydroxymethyl, protected hydroxymethyl,amino, protected amino, (monosubstituted)amino, protected(monosubstituted)amino, (disubstituted)amino, carboxamide, protectedcarboxamide, C₁ to C₄ alkylthio, C₁ to C₄ substituted alkylthio, C₁ toC₄ alkylsulfonyl, C₁ to C₄ substituted alkylsulfonyl, C₁ to C₄alkylsulfoxide, C₁ to C₄ substituted alkylsulfoxide, phenylthio,substituted phenylthio, phenylsulfoxide, substituted phenylsulfoxide,phenylsulfonyl or substituted phenylsulfonyl;

R⁵ is hydrogen, C₁ to C₁₀ alkyl, C₂ to C₁₀ substituted alkyl, C₂ to C₁₀alkenyl, C₂ to C₁₀ substituted alkenyl, C₂ to C₁₀ alkynyl, C₂ to C₁₀substituted alkynyl, C₃ to C₇ cycloalkyl, C₃ to C₇ substitutedcycloalkyl, C₅ to C₇ cycloalkenyl, C₅ to C₇ substituted cycloalkenyl,phenyl, substituted phenyl, naphthyl, substituted naphthyl, C₇ to C₁₂phenylalkyl, C₇ to C₁₂ substituted phenylalkyl, carboxy, protectedcarboxy, C₁ to C₇ acyl, C₁ to C₇ substituted acyl, heterocyclic ring,substituted heterocyclic ring, heteroaryl ring or substituted heteroarylring;

R⁶ is a hydrogen atom, C₁₀ to C₁₀ alkyl, C₁ to C₁₀ substituted alkyl, C₇to C₁₂ phenylalkyl, C₇ to C₁₂ substituted phenylalkyl, C₁ to C₇ acyl, C₁to C₇ substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, C,to C₄ alkylsulfonyl, C₁ to C₄ substituted alkylsulfonyl, C₁ to C₆alkylaminocarbonyl, C₁ to C₆ substituted alkylaminocarbonyl,phenylaminocarbonyl, or substituted phenylaminocarbonyl;

n is 1 to 3;and

Y is CO₂ H, OH, SH, NHR₇, C(O)NHR⁷, CH₂ OH, CH₂ NH₂, or CH₂ NHR⁷,wherein R⁷ is a hydrogen atom, C₁ to C₁₀ alkyl, C₁ to C₁₀ substitutedalkyl, or a functionalized resin, providing that when Y is CO₂ H that R¹is not absent and R¹ is not phenyl, and more preferably, Y is CO₂ H,NHR⁷ or C(O)NHR⁷, wherein R⁷ is a hydrogen atom, C₁ to C₁₀ alkyl, C₁ toC₁₀ substituted alkyl, or a functionalized resin, providing that when Yis CO₂ H that R¹ is not absent and R⁵ is not phenyl.

For R¹ defined above, p and q are independently selected from a number 0to 6. Preferably, p and q are independently selected from 0 to 4 and,more preferably, from 0 to 3.

In one embodiment of the invention the tricyclic tetrahydroquinolinecompounds and libraries containing the same are wherein:

R¹ is absent or present and, when present, is C₁ to C₁₀ alkylene, C₁ toC₁₀ substituted alkylene, phenylene, substituted phenylene, or a groupof the formula: --CH₂ C(O)NH--;

R², R³, and R⁴ are, independently, selected from a hydrogen atom, halo,hydroxy, protected hydroxy, nitro, C₁ to C₁₀ alkyl, C₁ to C₇ alkoxy, orcyclic C₂ to C₇ alkylene;

R⁵ is hydrogen atom, C₁ to C₁₀ alkyl, C₁ to C₁₀ substituted alkyl, C₂ toC₇ alkenyl, C₂ to C₇ substituted alkenyl, phenyl, substituted phenyl,naphthyl, substituted naphthyl, C₃ to C₇ cycloalkyl, C₃ to C₇substituted cycloalkyl, C₇ to C₁₂ phenylalkyl, C₇ to C₁₂ substitutedphenylalkyl, C₅ to C₇ cylcoalkenyl, C₅ to C₇ substituted cycloalkenyl,heterocyclic ring, substituted heterocyclic ring, heteroaryl,substituted heteroaryl, C₁ to C₇ acyl, substituted acyl, carboxy orprotected carboxy;

R⁶ is a hydrogen atom;

n is 1 to 2;and

Y is C(O)NHR⁷, wherein R⁷ is a hydrogen atom or a functionalized resin.

In another embodiment, the tricyclic tetrahydroquinoline compounds andlibraries containing the same are wherein:

R¹ is absent or present and, when present, is --CH₂ NHCO-- or --CH₂CH(NHR⁸)--, wherein R⁸ is selected from a hydrogen atom, C₁ to C₁₀alkyl, C₁ to C₁₀ substituted alkyl, C₂ to C₁₀ alkenyl, C₂ to C₁₀substituted alkenyl, C₂ to C₁₀ alkynyl, C₂ to C₁₀ substituted alkynyl,C₇ to C₁₂ phenylalkyl, C₇ to C₁₂ substituted phenylalkyl, C₁ to C₇ acyl,C₁ to C₇ substituted acyl, aminocarbonyl, protected aminocarbonyl,(monosubstituted)aminocarbonyl, protected(monosubstitituted)aminocarbonyl, (disubstituted)aminocarbonyl, C₁ to C₇alkylsulfonyl, C₇ to C₁₂ phenylalkylsulfonyl, phenylsulfonyl orsubstituted phenylsulfonyl;

R², R³, and R⁴ are each, independently, a hydrogen atom, nitro, hydroxy,halo, C₁ to C₁₀ alkyl, C₁ to C₆ alkoxy, or cyclic C₂ to C₇ alkylene;

R⁵ is a hydrogen atom, carboxy, C₁ to C₁₀ alkyl, C₁ to C₁₀ substitutedalkyl, C₂ to C₁₀ alkenyl, C₂ to C₁₀ substituted alkenyl, C₃ to C₈cycloalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl,heterocyclic ring, substituted heterocyclic ring, heteroaryl ring orsubstituted heteroaryl ring;

n is equal to 1;

R⁶ is a hydrogen atom; and

Y is C(O)NH₂ or C(O)NH bound to a functionalized resin.

In yet another embodiment, as exemplified in Example 1 below,

R¹ is absent or CH₂ NHCO;

R², R³, and R⁴ are each, independently, a hydrogen atom, hydroxy,fluoro, chloro, bromo, iodo, methyl, methoxy, nitro or --CH═CH--CH═CH--fused to adjacent positions;

R⁵ is a hydrogen atom, phenyl, chloromethyl, cyclohexanyl,d,1-1,2-(dihydroxy)ethyl, carboxy, acetyl, 2-hydroxyphenyl,tribromomethyl, trimethylacetyl, 1-methyl-2-pyrrolyl, 1-napthyl,2,3,4-trifluorophenyl, 2,3,5-trichlorophenyl, 2,3-difluorophenyl,2,4-dichlorophenyl, 2,5-difluorophenyl, 2,5-dimethylphenyl,2,6-difluorophenyl, 2-bromophenyl, 2-chloro-5-nitrophenyl,2-chloro-6-fluorophenyl, 2-cyanophenyl, 2-ethylbutyryl, 2-fluorophenyl,2-(2-oxymethylenecarboxy)phenyl, 2-methoxy-1-naphthyl,2-nitro-5-chlorophenyl, 2-nitrophenyl, 2-pyridinyl,3,4-(methylenedioxy)-6-nitrophenyl, 3,4-difluorophenyl,3,5-bis(trifluoromethyl)phenyl, 3,5-dichlorophenyl,3-(3,4-dichlorophenoxy)phenyl, 3-bromo-4-fluorophenyl, 3-bromophenyl,3-carboxyphenyl, 3-cyanophenyl, 3-fluorophenyl, 3-chromonyl, 3-furyl,3-hydroxyphenyl, 3-nitro-4-chlorophenyl, 3-nitrophenyl, 3-phenoxyphenyl,2-phenylpropyl, 3-pyridinyl, 4-bromo-2-thiophene-yl, 4-bromophenyl,4-carboxyphenyl, 4-cyanophenyl, 4-fluorophenyl, 4-nitrophenyl,4-pyridinyl, 4-quinolinyl, 5-bromo-2-hydroxyphenyl, 5-nitro-2-furyl,5-norbomene-2-yl, 6-methyl-2-pyridinyl, 9-ethyl-3-carbazolyl,1,2-dimethylbutyryl, 1,1-dimethyl-3-butenyl, 3-methoxy-2-nitro-phenyl,3-hydroxy-4-nitrophenyl, 1-methylpropyl, 1-methylbutyl,4-chloro-3-nitrophenyl, 4-(trifluoromethyl)phenyl, 1-methyldecanyl, orβ-phenylcinnaminyl;

R⁶ is a hydrogen atom;

n is 1; and

Y is C(O)NH₂ or C(O)NH bound to a functionalized resin.

In a further preferred embodiment, exemplified in Example 2,

R¹ is CH₂ CH(NHR⁸) wherein R⁸ is acetyl, butyryl, cyclobutanecarbonyl,cycloheptanecarbonyl, 4-cyclohexanebutyryl, cyclohexanecarbonyl,3-cyclohexanepropionyl, cyclohexylacetyl, cyclopentanecarbonyl,cyclopentylacetyl, hydrocinnamyl, isobutyryl, isovaleryl, octanoyl,propionyl, tert-butylacetyl, trimethylacetyl, 1-adamantaneacetyl,4-methyl-1-cyclohexanecarbonyl, 4-methylcyclohexaneacetyl,4-methylvaleryl, 2-ethyl-2-hexenoyl, 2-ethylbutyryl, 2-ethylhexanoyl,2-methylbutyryl, 2-methylcyclopropanecarbonyl, 2-norbornaneacetyl,2-phenylbutyryl, 2-propylpentanoyl, 3,3,3-triphenylpropionyl,3,3-diphenylpropionyl, 4-tert-butyl-cyclohexanecarbonyl,3,5,5-trimethylhexanoyl, 5-phenylvaleryl, 3-(2-methoxyphenyl)propionyl,3-(3,4,5-trimethoxyphenyl)propionyl, 3-(3,4-dimethoxyphenyl)propionyl,heptanoyl, 3-cyclopentylpropionyl, formyl, lauryl, 3-methylvaleryl,3-phenylbutyryl, α-cyclohexylphenylacetyl, α-methylcinnamyl, crotonyl,ethoxyacetyl, 4-chlorocinnamyl, 4-ethoxyphenylacetyl, m-tolylacetyl,methoxyacetyl, p-tolylacetyl, phenoxyacetyl, phenylacetyl, tiglyl,trans-3-hexenoyl, trans-cinnamyl, trans-styrylacetyl, triphenylacetyl,4-fluorophenylacetyl, vinylacetyl, (2,5-dimethoxyphenyl)acetyl,(2-naphthoxy)acetyl, (3,4-dimethoxyphenyl)acetyl,(α-α-α-trifluoro-m-tolyl)acetyl, (methylthio)acetyl,1-(4-chlorophenyl)-1-cyclopentanecarbonyl, 1-naphthylacetyl,1-phenyl-1-cyclopropanecarbonyl, 4-isobutyl-α-methylphenylacetyl,4-methoxyphenylacetyl, 2,4-hexadienoyl, 2-(trifluoromethyl)-cinnamyl,2-chloro-4-fluorophenylacetyl, 2-naphthylacetyl,3,4,5-trimethoxycinnamyl, 3,4-dichlorophenylacetyl, 3,4-dimethylbenzoyl,3,4,5-trimethoxyphenylacetyl, 3-benzoylpropionyl, 3-bromophenylacetyl,3-fluorophenylacetyl, 3-methoxyphenylacetyl, 3-thiopheneacetyl,4-biphenylacetyl, 4-bromophenylacetyl, α,α,α-trifluoro-m-toluyl,α,α,α-trifluoro-o-toluyl, benzoyl, niflumyl, o-anisyl, o-toluyl,piperonylyl, 1-napthoyl, 2,3-dichlorobenzoyl, 2,3-dimethoxybenzoyl,2,4-dichlorobenzoyl, 2,4-difluorobenzoyl, 2,4-dimethoxybenzoyl,2,4-dimethylbenzoyl, 2,5-dichlorobenzoyl, 2,5-dimethylbenzoyl,2,6-dychlorobenzoyl, 2,6-difluorobenzoyl, 2,6-dimethoxybenzoyl,2-bromobenzoyl, 2-chloro-4,5-difluorobenzoyl, 2-chlorobenzoyl,2-ethoxybenzoyl, 2-fluorobenzoyl, 2-napthoyl, 3,4,5-triethoxybenzoyl,3,4,5-trimethoxybenzoyl, 3,4-dichlorobenzoyl, 3,4-difluorobenzoyl,3,4-dimethoxybenzoyl, 3,5-bis(trifluoromethyl)benzoyl,5-bromo-2-chlorobenzoyl, 3,5-dimethyl-p-anisyl, 3-bromobenzoyl,3-chlorobenzoyl, 3-cyanobenzoyl, 3-(dimethylamino)benzoyl,3-fluoro-4-methylbenzoyl, 3-fluorobenzoyl, 3-iodo-4-methylbenzoyl,3-phenoxybenzoyl, 4-chloro-o-anisyl, α,α,α-trifluoro-p-toluyl,4-cyanobenzoyl, 4-(dimethylamino)benzoyl, 4-ethoxybenzoyl, isonicotinyl,4-ethylbenzoyl, m-anisyl, m-toluyl, nicotinyl, p-anisyl, p-toluyl,picolinyl, pyrrole-2-carbonyl, 4-fluorobenzoyl, 4-isopropoxybenzoyl,tetrahydro-2-furoyl, tetrahydro-3-furoyl, trans-3-(3-pyridyl)acrylyl,xanthene-9-carbonyl, (4-pyridylthio)acetyl, (phenylthio)acetyl,4-iodobenzoyl, 4-isopropylbenzoyl, 2-furoyl, 2-pyrazinecarbonyl,2-thiopheneacetyl, 2-thiophenecarbonyl, 5-bromonicotinyl,3,5-dichlorobenzoyl, 6-chloronicotinyl, 3,5-dimethoxybenzoyl,3,5-dimethylbenzoyl, chromone-2-carbonyl, 1-isoquinolinecarbonyl,3-methyl-2-thiophene-yl, 4'-ethyl-4-biphenylcarbonyl,4-(diethylamino)benzoyl, 4-benzoylbenzoyl, 4-biphenylcarbonyl,4-bromobenzoyl, 4-butylbenzoyl, or 4-chlorobenzoyl;

R² R³, and R⁴ are each, independently, a hydrogen atom;

R⁵ is a carboxy, 1-napthyl, 2,3,4-trifluorophenyl,2,3,5-trichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl,2,5-difluorophenyl, 2,5-dimethylphenyl, 2,6-difluorophenyl,2-bromophenyl, 2-chloro-5-nitrophenyl, 2-fluorophenyl,3,4-(methylenedioxy)-6-nitrophenyl, 3,4-difluorophenyl,3,5-bis(trifluoromethyl)phenyl, 3,5-dichlorophenyl, 3-cyanophenyl,3-fluorophenyl, 3-chromonyl, 3-nitro-4-chlorophenyl, 3-phenoxyphenyl,4-cyanophenyl, 4-pyridinyl, 3-methoxy-2-nitrophenyl, or3-hydroxy-4-nitrophenyl;

R⁶ is a hydrogen atom;

n is 1; and

Y is C(O)NH₂ or C(O)NH bound to a functionalized resin.

In an alternative embodiment,

R¹ is absent or present and, when present, is --CH₂ NHCO-- or CH₂CH(NHR⁸) wherein R¹ is acetyl, butyryl, cyclobutanecarbonyl,cycloheptanecarbonyl, 4-cyclohexanebutyryl, cyclohexanecarbonyl,3-cyclohexanepropionyl, cyclohexylacetyl, cyclopentanecarbonyl,cyclopentylacetyl, hydrocinnamyl, isobutyryl, isovaleryl, octanoyl,propionyl, tert-butylacetyl, trimethylacetyl, 1-adamantaneacetyl,4-methyl-1-cyclohexanecarbonyl, 4-methylcyclohexaneacetyl,4-methylvaleryl, 2-ethyl-2-hexenoyl, 2-ethylbutyryl, 2-ethylhexanoyl,2-methylbutyryl, 2-methylcyclopropanecarbonyl, 2-norbornaneacetyl,2-phenylbutyryl, 2-propylpentanoyl, 3,3,3-triphenylpropionyl,3,3-diphenylpropionyl, 4-tert-butyl-cyclohexanecarbonyl,3,5,5-trimethylhexanoyl, 5-phenylvaleryl, 3-(2-methoxyphenyl)propionyl,3-(3,4,5-trimethoxyphenyl)propionyl, 3-(3,4-dimethoxyphenyl)propionyl,heptanoyl, 3-cyclopentylpropionyl, formyl, lauryl, 3-methylvaleryl,3-phenylbutyryl, α-cyclohexylphenylacetyl, α-methylcinnamyl, crotonyl,ethoxyacetyl, 4-chlorocinnamyl, 4-ethoxyphenylacetyl, m-tolylacetyl,methoxyacetyl, p-tolylacetyl, phenoxyacetyl, phenylacetyl, tiglyl,trans-3-hexenoyl, trans-cinnamyl, trans-styrylacetyl, triphenylacetyl,4-fluorophenylacetyl, vinylacetyl, (2,5-dimethoxyphenyl)acetyl,(2-naphthoxy)acetyl, (3,4-dimethoxyphenyl)acetyl,(α-α-α-trifluoro-m-tolyl)acetyl, (methylthio)acetyl,1-(4-chlorophenyl)-1-cyclopentanecarbonyl, 1-naphthylacetyl,1-phenyl-1-cyclopropanecarbonyl, 4-isobutyl-a-methylphenylacetyl,4-methoxyphenylacetyl, 2,4-hexadienoyl, 2-(trifluoromethyl)-cinnamyl,2-chloro-4-fluorophenylacetyl, 2-naphthylacetyl,3,4,5-trimethoxycinnamyl, 3,4-dichlorophenylacetyl, 3,4-dimethylbenzoyl,3,4,5-trimethoxyphenylacetyl, 3-benzoylpropionyl, 3-bromophenylacetyl,3-fluorophenylacetyl, 3-methoxyphenylacetyl, 3-thiopheneacetyl,4-biphenylacetyl, 4-bromophenylacetyl, α,α,α-trifluoro-m-toluyl,α,α,α-trifluoro-o-toluyl, benzoyl, niflumyl, o-anisyl, o-toluyl,piperonylyl, 1-napthoyl, 2,3-dichlorobenzoyl, 2,3-dimethoxybenzoyl,2,4-dichlorobenzoyl, 2,4-difluorobenzoyl, 2,4-dimethoxybenzoyl,2,4-dimethylbenzoyl, 2,5-dichlorobenzoyl, 2,5-dimethylbenzoyl,2,6-dychlorobenzoyl, 2,6-difluorobenzoyl, 2,6-dimethoxybenzoyl,2-bromobenzoyl, 2-chloro-4,5-difluorobenzoyl, 2-chlorobenzoyl,2-ethoxybenzoyl, 2-fluorobenzoyl, 2-napthoyl, 3,4,5-triethoxybenzoyl,3,4,5-trimethoxybenzoyl, 3,4-dichlorobenzoyl, 3,4-difluorobenzoyl,3,4-dimethoxybenzoyl, 3,5-bis(trifluoromethyl)benzoyl,5-bromo-2-chlorobenzoyl, 3,5-dimethyl-p-anisyl, 3-bromobenzoyl,3-chlorobenzoyl, 3-cyanobenzoyl, 3-(dimethylamino)benzoyl,3-fluoro-4-methylbenzoyl, 3-fluorobenzoyl, 3-iodo-4-methylbenzoyl,3-phenoxybenzoyl, 4-chloro-o-anisyl, α,α,α-trifluoro-p-toluyl,4-cyanobenzoyl, 4-(dimethylamino)benzoyl, 4-ethoxybenzoyl, isonicotinyl,4-ethylbenzoyl, m-anisyl, m-toluyl, nicotinyl, p-anisyl, p-toluyl,picolinyl, pyrrole-2-carbonyl, 4-fluorobenzoyl, 4-isopropoxybenzoyl,tetrahydro-2-furoyl, tetrahydro-3-furoyl, trans-3-(3-pyridyl)acrylyl,xanthene-9-carbonyl, (4-pyridylthio)acetyl, (phenylthio)acetyl,4-iodobenzoyl, 4-isopropylbenzoyl, 2-furoyl, 2-pyrazinecarbonyl,2-thiopheneacetyl, 2-thiophenecarbonyl, 5-bromonicotinyl,3,5-dichlorobenzoyl, 6-chloronicotinyl, 3,5-dimethoxybenzoyl,3,5-dimethylbenzoyl, chromone-2-carbonyl, 1-isoquinolinecarbonyl,3-methyl-2-thiophene-yl, 4'-ethyl-4-biphenylcarbonyl,4-(diethylamino)benzoyl, 4-benzoylbenzoyl, 4-biphenylcarbonyl,4-bromobenzoyl, 4-butylbenzoyl, or 4-chlorobenzoyl;

R², R³, and R⁴ are each, independently, a hydrogen atom, hydroxy,fluoro, chloro, bromo, iodo, methyl, methoxy, nitro or --CH═CH--CH═CH--fused to adjacent positions;

R⁵ is a a hydrogen atom, phenyl, chloromethyl, cyclohexanyl,d,1-1,2-(dihydroxy)ethyl, carboxy, acetyl, 2-hydroxyphenyl,tribromomethyl, trimethylacetyl, 1-methyl-2-pyrrolyl, 1-napthyl,2,3,4-trifluorophenyl, 2,3,5-trichlorophenyl, 2,3-difluorophenyl,2,4-dichlorophenyl, 2,5-difluorophenyl, 2,5-dimethylphenyl,2,6-difluorophenyl, 2-bromophenyl, 2-chloro-5-nitrophenyl,2-chloro-6-fluorophenyl, 2-cyanophenyl, 2-ethylbutyryl, 2-fluorophenyl,2-(2-oxymethylenecarboxy)phenyl, 2-methoxy-1-naphthyl,2-nitro-5-chlorophenyl, 2-nitrophenyl, 2-pyridinyl,3,4-(methylenedioxy)-6-nitrophenyl, 3,4-difluorophenyl,3,5-bis(trifluoromethyl)phenyl, 3,5-dichlorophenyl,3-(3,4-dichlorophenoxy)phenyl, 3-bromo-4-fluorophenyl, 3-bromophenyl,3-carboxyphenyl, 3-cyanophenyl, 3-fluorophenyl, 3-chromonyl, 3-furyl,3-hydroxyphenyl, 3-nitro-4-chlorophenyl, 3-nitrophenyl, 3-phenoxyphenyl,2-phenylpropyl, 3-pyridinyl, 4-bromo-2-thiophene-yl, 4-bromophenyl,4-carboxyphenyl, 4-cyanophenyl, 4-fluorophenyl, 4-nitrophenyl,4-pyridinyl, 4-quinolinyl, 5-bromo-2-hydroxyphenyl, 5-nitro-2-furyl,5-norbornene-2-yl, 6-methyl-2-pyridinyl, 9-ethyl-3-carbazolyl,1,2-dimethylbutyryl, 1,1-dimethyl-3-butenyl, 3-methoxy-2-nitro-phenyl,3-hydroxy-4-nitrophenyl, 1-methylpropyl, 1-methylbutyl,4-chloro-3-nitrophenyl, 4-(trifluoromethyl)phenyl, 1-methyldecanyl, orβ-phenylcinnaminyl;

R⁶ is nalidixoyl, 2-phenyl-4-quinolinecarboxy, 2-pyrazinecarboxy,niflumoyl, 4-nitrophenylacetyl, 4-(4-nitrophenyl)butyroyl,(3,4-dimethoxyphenyl)acetyl, 3,4-(methylenedioxy)phenylacetyl,4-nitrocinnamoyl, 3,4-(methylenedioxy)cinnamoyl,3,4,5-trimethoxycinnamoyl, benzoyl, 2-chlorobenzoyl, 2-nitrobenzoyl,2-(p-toluoyl)benzoyl, 2,4-dinitrophenylacetyl,3-(3,4,5-trimethoxyphenyl)-propionyl, 4-biphenylacetyl, 1-napthylacetyl,(2-napthoxy)acetyl, trans-cinnamoyl, picolinyl,3-amino-4-hydroxybenzoyl, (4-pyridylthio)acetyl, 2,4-dichlorobenzoyl,3,4-dichlorobenzoyl, 4-biphenylcarboxy, thiophenoxyacetyl,1-benzoylpropionyl, phenylacetyl, hydrocinnamoyl, 3,3-diphenylpropionyl,3,3,3-triphenylpropionyl, 4-phenylbutyryl, phenoxyacetyl,(+/-)-2-phenoxypropionyl, 2,4-dimethoxybenzoyl, 3,4-dimethoxybenzoyl,3,4-dihydroxybenzoyl, 2,4-dihydroxybenzoyl, 3,4,5-trimethoxybenzoyl,3,4,5-triethoxybenzoyl, 3,4,5-trihydroxybenzoyl, 2-benzoylbenzoyl,1-napthoyl, xanthene-9-carboxy, 4-chloro-2-nitrobenzoyl,2-chloro-4-nitrobenzoyl, 4-chloro-3-nitrobenzoyl,2-chloro-5-nitrobenzoyl, 4-(dimethylamino)benzoyl,4-(diethylamino)benzoyl, 4-nitrobenzoyl, 3-(dimethylamino)benzoyl,p-methylbenzoyl, p-methoxybenzoyl, trimethylacetyl, tert-butylacetyl,(-)-menthoxyacetyl, cyclohexanecarboxy, cyclohexylacetyl,dicyclohexylacetyl, 4-cyclohexylbutyroyl, cycloheptanecarboxy,13-isopropylpodocarpa-7,13-dien-15-oyl, acetyl, octanoyl,(methylthio)acetyl, 3-nitropropionyl, 4-amino-3 hydroxybenzoyl,3-(2-methyl-4-nitro-1-imidizoyl)propionyl, 2-furoyl,(s)(-)-2-pyrrolidone-5-carboxy, (2-pyrimidylthio)acetyl,4-methoxy-2-quinolinecarboxy, 1-adamantanecarboxy, piperonoyl,5-methyl-3-phenylisoxazole-4-carboxy, rhodanine-3-acetyl,2-norbornaneacetyl, nicotinoyl, 9-oxo-9H-thioxanthene-3-carboxyl-10,10dioxide, 2-thiophenecarboxy, 5-nitro-2-furanoyl, indole-3-acetyl,isonicotinoyl, 3a-hydroxy-5β-cholan-24-oyl,(3α,7α,12α)-trihydroxy-5β-cholan-24-oyl, (3α, 5β-12α)-3,12,dihydroxy-5-cholan-24-oyl, (3α, 5β, 6α)-3,6-dihydroxy-cholan-24-oyl,L-alaninyl, L-cysteinyl, L-aspartinyl, L-glutaminyl, L-phenylalaninyl,glycinyl, L-histidinyl, L-isoleucinyl, L-lyscinyl, L-leucinyl,L-methionylsulfoxide, L-methionyl, L-asparginyl, L-prolinyl,L-glutaminyl, L-arganinyl, L-serinyl, L-threoninyl, L-valinyl,L-tryptophanoyl, L-tyrosinyl, D-alaninyl, D-cysteinyl, D-aspartinyl,D-glutaminyl, D-phenylalaninyl, glycinyl, D-histidinyl, D-isoleucinyl,D-lyscinyl, D-leucinyl, D-methionylsulfoxide, D-methionyl, D-asparginyl,D-prolinyl, D-glutaminyl, D-arganinyl, D-serinyl, D-threoninyl,D-valinyl, -D-tryptophanoyl, D-tyrosinyl, 2-aminobutyroyl,4-aminobutyroyl, 2-aminoisobutyroyl, L-norleucinyl, D-norleucinyl,6-aminohexanoyl, 7-aminoheptanoyl, thioprolinyl, L-norvalinyl,D-norvalinyl, α-omithinyl, methionyl sulfonyl, L-naphthylalaninyl,D-naphthylalaninyl, L-phenylglycinyl, D-phenylglycinyl, β-alaninyl,L-cyclohexylalaninyl, D-cyclohexylalaninyl, hydroxyprolinyl,4-nitrophenylalaninyl, dehydroprolinyl, 3-hydroxy-1-propanesulfonyl,1-propanesulfonyl, 1-octanesulfonyl, perfluoro-1-octanesulfonly,(+)-10-camphorsulfonyl, (-)-10-camphorsulfonyl, benzenesulfonyl,2-nitrobenzenesulfonyl, p-toluenesulfonyl, 4-nitrobenzenesulfonyl,n-acetylsulfanilyl, 2,5-dichlorobenzenesulfonyl,2,4-dinitrobenzenesulfonyl, 2-mesitylenesulfonyl or2-napthalenesulfonyl;

n is 1; and

Y is C(O)NH₂ or C(O)NH bound to a functionalized resin.

In the above Formula I, the R¹ --Y substituents are such that Y isalways bonded to the 1-position of the R¹ radical. All naming above andhereinafter reflects this positioning between the two substituents.

In the above Formula I, the stereochemistry of chiral centers associatedwith the R¹ through R⁸ groups can independently be in the R or Sconfiguration, or a mixture of the two. These can be designated as R orS or R,S or d,D, 1,L or d,1, D,L.

In the above Formula I, the term "C₁ to C₁₀ alkyl" denotes such radicalsas methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,amyl, tert-amyl, hexyl and the like. The preferred "C₁ to C₁₀ alkyl"group is methyl.

The term "C₂ to C₁₀ alkenyl" denotes such radicals as vinyl, allyl,2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl,3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl,5-heptenyl, 6-heptenyl, as well as dienes and trienes of straight andbranched chains.

The term "C₂ to C₁₀ alkynyl" denotes such radicals as ethynyl, propynyl,butynyl, pentynyl, hexynyl, heptynyl, as well as di- and tri-ynes ofstraight and branched chains.

The term "C₁ to C₁₀ alkylene" means a C₁ to C₁₀ alkyl group where thealkyl radical is bonded at two positions connecting together twoseparate additional groups. Examples of C₁ to C₁₀ alkylene includemethylene, 1,2-ethyl, 1,1-ethyl, 1,3-propyl and the like. The term "C₂to C₁₀ alkenylene" means a C₂ to C₁₀ alkenyl radican which is bonded attwo positions connecting is together two separate additional groups.

The terms "C₁ to C₁₀ substituted alkyl," "C₂ to C₁₀ substitutedalkenyl," and "C₂ to C₁₀ substituted alkynyl," denote that the above C₁to C₁₀ alkyl groups and C₂ to C₁₀ alkenyl and alkynyl groups aresubstituted by one or more, and preferably one or two, halogen, hydroxy,protected hydroxy, oxo, protected oxo, cyclohexyl, naphthyl, amino,protected amino, (monosubstituted)amino, protected(monosubstituted)amino, (disubstituted)amino, guanidino, heterocyclicring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl,C₁ to C₇ alkoxy, C₁ to C₇ acyl, C₁ to C₇ acyloxy, nitro, C₁ to C₇ alkylester, carboxy, protected carboxy, carbamoyl, carboxamide, protectedcarboxamide, N'(C₁ to C₆ alkyl)carboxamide, protected N-(C₁ to C₆₋₋alkyl)carboxamide, N,N-di(C₁ to C₆ alkyl)carboxamide, cyano,methylsulfonylamino, thio, C₁ to C₄ alkylthio or C₁ to C₄ alkyl sulfonylgroups. The substituted alkyl, alkenyl or alkynyl groups may besubstituted once or more, and preferably once or twice, with the same orwith different substituents.

Examples of the above substituted alkyl groups include the2-oxo-prop-1-yl, 3-oxo-but-1-yl, cyanomethyl, nitromethyl, chloromethyl,hydroxymethyl, tetrahydropyranyloxymethyl, trityloxymethyl,propionyloxymethyl, amino, methylamino, aminomethyl, dimethylamino,carboxymethyl, allyloxycarbonylmethyl, allyloxycarbonylaminomethyl,methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl,chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl,2,4-dichloro(n-butyl), 2-aminopropyl, chloroethyl, bromoethyl,fluoroethyl, iodoethyl, chloropropyl, bromopropyl, fluoropropyl,iodopropyl, 2-aminoethyl, 1-aminoethyl, N-benzoyl-2-aminoethyl,N-acetyl-2-aminoethyl, N-benzoyl-1-aminoethyl, N-acetyl-1-aminoethyl andthe like.

Examples of the above substituted alkenyl groups include styrenyl,3-chloro-propen-1-yl, 3-chloro-buten-1-yl, 3-methoxy-propen-2-yl,3-phenyl-buten-2-yl, 1-cyano-buten-3-yl and the like. The geometricalisomerism is not critical, and all geometrical isomers for a givensubstituted alkenyl can be used.

Examples of the above substituted alkynyl groups includephenylacetylen-1-yl, 1-phenyl-2-propyn-1-yl and the like.

In preferred embodiments of the subject invention C₁ to C₁₀ alkyl, C₂ toC₁₀ alkenyl, C₂ to C₁₀ alkynyl, C₁ to C₁₀ substituted alkyl, C₂ to C₁₀substituted alkenyl, or C₂ to C₁₀ substituted alkynyl are preferably C₁to C₇ or C₂ to C₈, respectively, and more preferably, C₁ to C₆ and C₂ toC₇. However, it should be appreciated by those of skill in the art thatone or a few carbons could be added to an alkyl, alkenyl, alkynyl,substituted or unsubstituted, without substantially modifying thestructure and function of the subject compounds and that, therefore,such additions would not depart from the spirit of the invention.

The term "C₁ to C₁₀ substituted alkylene" means a C₁ to C₁₀ alkyl groupwhere the alkyl radical is bonded at two positions connecting togethertwo separate additional groups and further bearing an additionalsubstituent. Examples of C₁ to C₁₀ substituted alkylene includeaminomethylene, 1-(amino)-1,2-ethyl, 2-(amino)-1,2-ethyl,1-(acetamido)-1,2-ethyl, 2-(acetamido)-1,2-ethyl, 2-hydroxy-1,1-ethyl,1-(amino)-3-propyl. Similarly, the term "C₂ to C₁₀ substitutedalkenylene" means a C₂ to C₁₀ substituted alkenyl group where thealkenyl radical is bonded at two positions connecting together twoseparate additional groups and further bearing an additionalsubstituent.

The term "oxo" denotes a carbon atom bonded to two additional carbonatoms substituted with an oxygen atom doubly bonded to the carbon atom,thereby forming a ketone moiety.

The term "protected oxo" denotes a carbon atom bonded to two additionalcarbon atoms substituted with two alkoxy groups or twice bonded to asubstituted diol moiety, thereby forming an acyclic or cyclic ketalmoiety.

The term "C₁ to C₇ alkoxy" as used herein denotes groups such asmethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and likegroups.

A preferred alkoxy is methoxy. The term "C₁ to C₇ substituted alkoxy"means the alkyl portion of the alkoxy can be substituted in the samemanner as in relation to C₁ to C₆ substituted alkyl.

The term "C₁ to C₇ acyloxy" denotes herein groups such as formyloxy,acetoxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy,heptanoyloxy and the like.

Similarly, the term "C₁ to C₇ acyl" encompasses groups such as formyl,acetyl, propionyl, butyryl, pentanoyl, pivaloyl, hexanoyl, heptanoyl,benzoyl and the like. Preferred acyl groups are acetyl and benzoyl.

The term "C₁ to C₇ substituted acyl" denotes the acyl group substitutedby one or more, and preferably one or two, halogen, hydroxy, protectedhydroxy, oxo, protected oxo, cyclohexyl, naphthyl, amino, protectedamino, (monosubstituted)amino, protected (monosubstituted)amino,(disubstituted)amino, guanidino, heterocyclic ring, substitutedheterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, C₁ to C₇ alkoxy,C₁ to C₇ acyl, C₁ to C₇ acyloxy, nitro, C₁ to C₇ alkyl ester, carboxy,protected carboxy, carbamoyl, carboxamide, protected carboxamide, N--(C₁to C₆ alkyl)carboxamide, protected N--(C₁ to C₆ alkyl)carboxamide,N,N-di(C₁ to C₆ alkyl)carboxamide, cyano, methylsulfonylamino, thio, C₁to C₄ alkylthio or C₁ to C₄ alkyl sulfonyl groups.

The substituted acyl groups may be substituted once or more, andpreferably once or twice, with the same or with different substituents.

Examples of C₁ to C₇ substituted acyl include 4-phenylbutyroyl,3-phenylbutyroyl, 3-phenylpropanoyl, 2-cyclohexanylacetyl,cyclohexanecarbonyl, 2-furanoyl and 3-(dimethylamino)benzoyl.

The substituent term "C₃ to C₇ cycloalkyl" includes the cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings. Thesubstituent term "C₃ to C₇ substituted cycloalkyl" indicates the abovecycloalkyl rings substituted by one or two halogen, hydroxy, protectedhydroxy, C₁ to C₆ alkyl, C₁ to C₇ alkoxy, oxo, protected oxo,(monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy,protected carboxy, phenyl, substituted phenyl, amino, or protected aminogroups.

The term "C₅ to C₇ cycloalkenyl" indicates a 1,2, or 3-cyclopentenylring, a 1,2,3 or 4-cyclohexenyl ring or a 1,2,3,4 or 5-cycloheptenylring, while the term "C₁ to C₇ substituted cycloalkenyl" denotes theabove C₅ to C₇ cycloalkenyl rings substituted by a C₁ to C₆ alkylradical, halogen, hydroxy, protected hydroxy, C₁ to C₇ alkoxy,trifluoromethyl, carboxy, protected carboxy, oxo, protected oxo,(monosubstituted)amino, protected (monosubstituted)amino,(disubstituted)amino, phenyl, substituted phenyl, amino, or protectedamino.

The term "heterocyclic ring" denotes optionally substitutedfive-membered or six-membered rings that have 1 to 4 heteroatoms, suchas oxygen, sulfur and/or nitrogen, in particular nitrogen, either aloneor in conjunction with sulfur or oxygen ring atoms. These five-memberedor six-membered rings may be saturated, fully saturated or partiallyunsaturated, with fully saturated rings being preferred. A "substitutedheterocyclic ring" means any of the above-described heterocyclessubstituted with any of the substituents as referred to above inrelation to substituted phenyl. An "amino-substituted heterocyclic ring"means any one of the above-described heterocyclic rings is substitutedwith at least one amino group. Preferred heterocyclic rings includemorpholino, piperidinyl, piperazinyl, tetrahydrofurano, pyrrolo, andtetrahydrothiophen-yl.

The abbreviation "Ar" stands for an aryl group. Aryl groups which can beused with present invention include phenyl, substituted phenyl, asdefined above, heteroaryl, and substituted heteroaryl. The term"heteroaryl" or "heteroaryl ring" means a heterocyclic aromaticderivative which is a five-membered or six-membered ring system havingfrom 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, inparticular nitrogen, either alone or in conjunction with sulfur oroxygen ring atoms. Examples of heteroaryls include pyridinyl,pyrimidinyl, and pyrazinyl, pyridazinyl, pyrrolo, furano, oxazolo,isoxazolo, thiazolo and the like.

The term "substituted heteroaryl" or "substituted heteroaryl ring" meansthe above-described heteroaryl is substituted with, for example, one ormore, and preferably one or two, substituents which are the same ordifferent which substituents can be halogen, hydroxy, protected hydroxy,cyano, nitro, C₁ to C₆ alkyl, C₁ to C₇ alkoxy, C₁ to C₇ substitutedalkoxy, C₁ to C₇ acyl, C₁ to C₇ acyloxy, carboxy, protected carboxy,carboxymethyl, protected carboxymethyl, hydroxymethyl, protectedhydroxymethyl, amino, protected amino, (monosubstituted)amino, protected(monosubstituted)amino, (disubstituted)amino carboxamide, protectedcarboxamide, N-(C₁ to C₆ alkyl)carboxamide, protected N-(C₁ to C₆alkyl)carboxamide, N, N-di(C₁ to C₆ alkyl)carboxamide, trifluoromethyl,N-((C₁ to C₆ alkyl)sulfonyl)amino or N-(phenylsulfonyl)amino groups.

The term "C₇ to C₁₂ phenylalkyl" denotes a C₁ to C₆ alkyl groupsubstituted at any position by a phenyl ring. Examples of such a groupinclude benzyl, 2-phenylethyl, 3-phenyl(n-propyl), 4-phenylhexyl,3-phenyl(n-amyl), 3-phenyl(sec-butyl) and the like. Preferred C₇ to C₁₂phenylalkyl groups are the benzyl and the phenylethyl groups.

The term "C₇ to C₁₂ substituted phenylalkyl" denotes a C₇ to C₁₂phenylalkyl group substituted on the C, to C₆ alkyl portion with one ormore, and preferably one or two, groups chosen from halogen, hydroxy,protected hydroxy, oxo, protected oxo, amino, protected amino,(monosubstituted)amino, protected (monosubstituted)amino,(disubstituted)amino, guanidino, heterocyclic ring, substitutedheterocyclic ring, C₁ to C₇ alkoxy, C₁ to C₇ substituted alkoxy, C₁ toC₇ acyl, C₁ to C₇ acyloxy, nitro, carboxy, protected carboxy, carbamoyl,carboxamide, protected carboxamide, N--(C₁ to C₆ alkyl)carboxamide,protected N--C₁ to C₆ alkyl)carboxamide, N,N--(C₁ to C₆dialkyl)carboxamide, cyano, N--((C₁ to C₆ alkylsulfonyl)amino, thiol, C₁to C₄ alkylthio, Cl to C₄ alkylsulfonyl groups; and/or the phenyl groupmay be substituted with one or more, and preferably one or two,substituents chosen from halogen, hydroxy, protected hydroxy, cyano,nitro, C₁ to C₆ alkyl, C₁ to C₇ alkoxy, C₁ to C₇ substituted alkoxy, C₁to C₇ acyl, C₁ to C₇ acyloxy, carboxy, protected carboxy, carboxymethyl,protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino,protected amino, (monosubstituted)amino, protected(monosubstituted)amino, (disubstituted)amino, carboxamide, protectedcarboxamide, N--(C₁ to C₆ alkyl) carboxamide, protected N--(C₁ to C₆alkyl) carboxamide, N,N-di(C₁ to C₆ alkyl)carboxamide, trifluoromethyl,N-((C₁ to C₆ alkyl)sulfonyl)amino, N-(phenylsulfonyl)amino, cyclic C₂ toC₇ alkylene or a phenyl group, substituted or unsubstituted, for aresulting biphenyl group. The substituted alkyl or phenyl groups may besubstituted with one or more, and preferably one or two, substituentswhich can be the same or different.

Examples of the term "C₇ to C₁₂ substituted phenylalkyl" include groupssuch as 2-phenyl-1-chloroethyl, 2-(4-methoxyphenyl)ethyl,4-(2,6-dihydroxy phenyl)n-hexyl, 2-(5-cyano-3-methoxyphenyl)n-pentyl,3-(2,6-dimethylphenyl)n-propyl, 4-chloro-3-aminobenzyl,6-(4-methoxyphenyl)-3-carboxy(n-hexyl),5-(4-aminomethylphenyl)-3-(aminomethyl)n-pentyl,5-phenyl-3-oxo-n-pent-1-yl and the like.

The term "substituted phenyl" specifies a phenyl group substituted withone or more, and preferably one or two, moieties chosen from the groupsconsisting of halogen, hydroxy, protected hydroxy, cyano, nitro, C₁ toC₆ alkyl, C₁ to C₇ alkoxy, C₁ to C₇ substituted alkoxy, Cl to C₇ acyl,C₁ to C₇ acyloxy, carboxy, protected carboxy, carboxymethyl, protectedcarboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protectedamino, (monosubstituted)amino, protected (monosubstituted)amino,(disubstituted)amino, carboxamide, protected carboxamide, N-(C₁ to C₆alkyl)carboxamide, protected N-(C₁ to C₆ alkyl)carboxamide, N, N-di(C₁to C₆ alkyl)carboxamide, trifluoromethyl, N-((C₁ to C₆alkyl)sulfonyl)amino, N-(phenylsulfonyl)amino or phenyl, substituted orunsubstituted, such that, for example, a biphenyl results.

Examples of the term "substituted phenyl" include a mono- ordi(halo)phenyl group such as 2, 3 or 4-chlorophenyl, 2,6-dichlorophenyl,2,5-dichlorophenyl, 3,4-dichlorophenyl, 2, 3 or 4-bromophenyl,3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2, 3 or 4-fluorophenyl andthe like; a mono or di(hydroxy)phenyl group such as 2, 3 or4-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivativesthereof and the like; a nitrophenyl group such as 2, 3 or 4-nitrophenyl;a cyanophenyl group, for example, 2, 3 or 4-cyanophenyl; a mono- ordi(alkyl)phenyl group such as 2, 3 or 4-methylphenyl,2,4-dimethylphenyl, 2, 3 or 4-(iso-propyl)phenyl, 2, 3 or 4-ethylphenyl,2, 3 or 4-(n-propyl)phenyl and the like; a mono or di(alkoxyl)phenylgroup, for example, 2,6-dimethoxyphenyl, 2, 3 or 4-methoxyphenyl, 2, 3or 4-ethoxyphenyl, 2, 3 or 4-(isopropoxy)phenyl, 2, 3 or4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 2, 3 or4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protectedcarboxy)phenyl group such as 2, 3 or 4-carboxyphenyl or 2,4-di(protectedcarboxy)phenyl; a mono-or di(hydroxymethyl)phenyl or (protectedhydroxymethyl)phenyl such as 2, 3, or 4-(protected hydroxymethyl)phenylor 3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl or(protected aminomethyl)phenyl such as 2, 3 or 4-(aminomethyl)phenyl or2,4-(protected aminomethyl)phenyl; or a mono- ordi(N-(methylsulfonylamino))phenyl such as 2, 3 or4-(N-(methylsulfonylamino))phenyl. Also, the term "substituted phenyl"represents disubstituted phenyl groups wherein the substituents aredifferent, for example, 3-methyl-4-hydroxyphenyl,3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl,4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy4-chlorophenyl and the like.

The term "phenylene" means a phenyl group where the phenyl radical isbonded at two positions connecting together two separate additionalgroups. Examples of phenylene include 1,2-phenyl, 1,3-phenyl, and1,4-phenyl.

The term "substituted phenylene" means a substituted phenyl group wherethe phenyl radical is bonded at two positions connecting together twoseparate additional groups. Examples of substituted phenylene include3-chloro-1,2-phenyl, 4-amino-1,3-phenyl, and 3-hydroxy-1,4-phenyl.

The term "phenoxy" denotes a phenyl bonded to an oxygen atom providedthat the phenoxy is bonded to the quinoline ring through the oxygen atomas opposed to a carbon atom of the phenyl ring. The term "substitutedphenoxy" specifies a phenoxy group substituted with one or more, andpreferably one or two, moieties chosen from the groups consisting ofhalogen, hydroxy, protected hydroxy, cyano, nitro, C₁ to C₆ alkyl, C₁ toC₇ alkoxy, C₁ to C₇ substituted alkoxy, C₁ to C₇ acyl, C₁ to C₇ acyloxy,carboxy, protected carboxy, carboxymethyl, protected carboxymethyl,hydroxymethyl, protected hydroxymethyl, amino, protected amino,(monosubstituted)amino, protected (monosubstituted)amino,(disubstituted)amino, carboxamide, protected carboxamide, N-(C₁ to C₆alkyl)carboxamide, protected N-(C₁ to C₆ alkyl)carboxamide, N, N-di(C₁to C₆ alkyl)carboxamide, trifluoromethyl, N-((C₁ to C₆alkyl)sulfonyl)amino and N-(phenylsulfonyl)amino.

Examples of substituted phenoxy include 2-methylphenoxy, 2-ethylphenoxy,2-propylphenoxy, 2-isopropylphenoxy, 2-sec-butylphenoxy,2-tert-butylphenoxy, 2-allylphenoxy, 2-propenylphenoxy,2-cyclopentylphenoxy, 2-fluorophenoxy, 2-(trifluoromethyl)phenoxy,2-chlorophenoxy, 2-bromophenoxy, 2-methoxyphenoxy, 2-ethoxyphenoxy,2-isopropoxyphenoxy, 3-methylphenoxy, 3-ethylphenoxy,3-isopropylphenoxy, 3-tert-butylphenoxy, 3-pentadecylphenoxy,3-(trifluoromethyl)phenoxy, 3-fluorophenoxy, 3-chlorophenoxy,3-bromophenoxy, 3-iodophenoxy, 3-methoxyphenoxy,3-(trifluoromethoxy)phenoxy, 4-methylphenoxy, 4-ethylphenoxy,4-propylphenoxy, 4-isopropylphenoxy, 4-sec-butylphenoxy,4-tert-butylphenoxy, 4-tert-amylphenoxy, 4-nonylphenoxy,4-dodecylphenoxy, 4-cyclopenylphenoxy, 4-(trifluoromethyl)phenoxy,4-fluorophenoxy, 4-chlorophenoxy, 4-bromophenoxy4-iodophenoxy,4-methoxyphenoxy, 4-(trifluoromethoxy)phenoxy, 4-ethoxyphenoxy,4-propoxyphenoxy, 4-butoxyphenoxy, 4-hexyloxyphenoxy,4-heptyloxyphenoxy, 2,3-dimethylphenoxy, 5,6,7,8-tetrahydro-1-naphthoxy,2,3-dichlorophenoxy, 2,3-dihydro-2,2-dimethyl-7-benzofuranoxy,2,3-dimethoxyphenoxy, 2,6-dimethylphenoxy, 2,6-diisopropylphenoxy,2,6-di-sec-butylphenoxy, 2-tert-butyl-6-methylphenoxy,2,6-di-tert-butylphenoxy, 2-allyl-6-methylphenoxy, 2,6-difluorophenoxy,2,3-difluorophenoxy, 2,6-dichlorophenoxy, 2,6-dibromophenoxy,2-fluoro-6-methoxyphenoxy, 2,6-dimethoxyphenoxy, 3,5-dimethylphenoxy,5-isopropyl-3-methylphenoxy, 3,5-di-tert-butylphenoxy,3,5-bis(trifluoromethyl)phenoxy, 3,5-difluorophenoxy,3,5-dichlorophenoxy, 3,5-dimethoxyphenoxy, 3-chloro-5-methoxyphenoxy,3,4-dimethylphenoxy, 5-indanoxy, 5,6,7,8-tetrahydro-2-naphthoxy,4-chloro-3-methylphenoxy, 2,4-dimethylphenoxy, 2,5-dimethylphenoxy,2-isopropyl-5-methylphenoxy, 4-isopropyl-3-methylphenoxy,5-isopropyl-2-methylphenoxy, 2-tert-butyl-5-methylphenoxy,2-tert-butyl-4-methylphenoxy, 2,4-di-tert-butylphenoxy,2,4-di-tert-amylphenoxy, 4-fluoro-2-methylphenoxy,4-fluoro-3-methylphenoxy, 2-chloro-4-methylphenoxy,2-chloro-5-methylphenoxy, 4-chloro-2-methylphenoxy,4-chloro-3-ethylphenoxy, 2-bromo-4-methylphenoxy, 4-iodomethylphenoxy,2-chloro-5-(trifluoromethyl)phenoxy, 2,4-difluorophenoxy,2,5-difluorophenoxy, 3,4-difluorophenoxy, 4-chloro-2-fluorophenoxy,3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy,2-bromo-4-fluorophenoxy, 4-bromo-2-fluorophenoxy,2-bromo-5-fluorophenoxy, 2,4-dichlorophenoxy, 3,4-dichlorophenoxy,2,5-dichlorophenoxy, 2-bromo-4-chlorophenoxy, 2-chloro-4-fluorophenoxy,4-bromo-2-chlorophenoxy, 2,4-dibromophenoxy, 2-methoxy-4-methylphenoxy,4-allyl-2-methylphenoxy, trans-2-ethoxy-5-(1-propenyl)phenoxy,2-methoxy-4-propenylphenoxy, 3,4-dimethoxyphenoxy,3-ethoxy-4-methoxyphenoxy, 4-allyl-2,6-dimethoxyphenoxy,3,4-methylenedioxyphenoxy, 2,3,6-trimethylphenoxy,2,4-dichloro-3-methylphenoxy, 2,3,4-trifluorophenoxy,2,3,6-trifluorophenoxy, 2,3,5-trifluorophenoxy, 2,3,4-trichlorophenoxy,2,3,6-trichlorophenoxy, 2,3,5-trimethylphenoxy, 3,4,5-trimethylphenoxy,4-chloro-3,5-dimethylphenoxy, 4-bromo-3,5-dimethylphenoxy,2,4,6-trimethylphenoxy, 2,6-bis(hydroxymethyl)-4-methylphenoxy,2,6-di-tert-butyl-4-methylphenoxy, 2,6-di-tert-butyl-4-methoxyphenoxy,2,4,5-trifluorophenoxy, 2-chloro-3,5-difluorophenoxy,2,4,6-trichlorophenoxy, 3,4,5-trimethoxyphenoxy, 2,3,5-trichlorophenoxy,4-bromo-2,6-dimethylphenoxy, 4-bromo-6-chloro-2-methylphenoxy,2,6-dibromo-4-methylphenoxy, 2,6-dichloro-4-fluorophenoxy,2,6-dibromo-4-fluorophenoxy, 2,4,6-tribromophenoxy,2,4,6-triiodophenoxy, 2-chloro-4,5-dimethylphenoxy,4-chloro-2-isopropyl-5-methylphenoxy, 2-bromo-4,5-difluorophenoxy,2,4,5-trichlorophenoxy, 2,3,5,6-tetrafluorophenoxy and the like.

The term "C₇ to C₁₂ phenylalkoxy" denotes a C₇ to C₁₂ phenylalkoxygroup, provided that the phenylalkoxy is bonded to the quinoline ringthrough the oxygen atom. By "C₇ to C₁₂ substituted phenylalkoxy" ismeant C₇ to C₁₂ phenylalkoxy group which can be substituted on the C₁ toC₆ alkyl portion with one or more, and preferably one or two, groupschosen from halogen, hydroxy, protected hydroxy, oxo, protected oxo,amino, protected amino, (monosubstituted)amino, protected(monosubstituted)amino, (disubstituted)amino, guanidino, heterocyclicring, substituted heterocyclic ring, C₁ to C₇ alkoxy, C₁ to C₇ acyl, C₁to C₇ acyloxy, nitro, carboxy, protected carboxy, carbamoyl,carboxamide, protected carboxamide, N-(C₁ to C₆ alkyl)carboxamide,protected N-C₁ to C₆ alkyl)carboxamide, N, N-(C₁ to C₆dialkyl)carboxamide, cyano, N-((C₁ to C₆ alkylsulfonyl)amino, thiol, C₁to C₄ alkylthio, C₁ to C₄ alkylsulfonyl groups; and/or the phenyl groupcan be substituted with one or more, and preferably one or two,substituents chosen from halogen, hydroxy, protected hydroxy, cyano,nitro, C₁ to C₆ alkyl, C₁ to C₇ alkoxy, C₁ to C₇ acyl, C₁ to C₇ acyloxy,carboxy, protected carboxy, carboxymethyl, protected carboxymethyl,hydroxymethyl, protected hydroxymethyl, amino, protected amino,(monosubstituted)amino, protected (monosubstituted)amino,(disubstituted)amino, carboxamide, protected carboxamide, N-(C₁ to C₆alkyl) carboxamide, protected N-(C₁ to C₆ alkyl) carboxamide, N, N-di(C₁to C₆ alkyl)carboxamide, trifluoromethyl, N-((C₁ to C₆alkyl)sulfonyl)amino, N-(phenylsulfonyl)amino or a phenyl group,substituted or unsubstituted, for a resulting biphenyl group. Thesubstituted alkyl or phenyl groups may be substituted with one or more,and preferably one or two, substituents which can be the same ordifferent.

Examples of the term "C₇ to C₁₂ substituted phenylalkoxy" include groupssuch as 2-(4-hydroxyphenyl)ethoxy, 4-(4-methoxyphenyl)butoxy,(2R)-3-phenyl-2-amino-propoxy, (2S)-3-phenyl-2-amino-propoxy,2-indanoxy, 6-phenyl-1-hexanoxy, cinnamyloxy, (+/-)-2-phenyl-1-propoxy,2,2-dimethyl-3-phenyl-1-propoxy and the like.

The term "phthalimide" means a cyclic imide which is made from phthalicacid, also called 1, 2 benezene-dicarboxylic acid. The term "substitutedphthalimide" specifies a phthalimide group substituted with one or more,and preferably one or two, moieties chosen from the groups consisting ofhalogen, hydroxy, protected hydroxy, cyano, nitro, C₁ to C₆ alkyl, C₁ toC₇ alkoxy, C₁ to C₇ substituted alkoxy, C₁ to C₇ acyl, C₁ to C₇ acyloxy,carboxy, protected carboxy, carboxymethyl, protected carboxymethyl,hydroxymethyl, protected hydroxymethyl, amino, protected amino,(monosubstituted)amino, protected (monosubstituted)amino,(disubstituted)amino, carboxamide, protected carboxamide, N-(C₁ to C₆alkyl)carboxamide, protected N-(C₁ to C₆ alkyl)carboxamide, N, N-di(C₁to C₆ alkyl)carboxamide, trifluoromethyl, N-((C₁ to C₆alkyl)sulfonyl)amino and N-(phenylsulfonyl)amino.

Examples of substituted phthalimides include 4,5-dichlorophthalimido,3-fluorophthalimido, 4-methoxyphthalimido, 3-methylphthalimido,4-carboxyphthalimido and the like.

The term "substituted naphthyl" specifies a naphthyl group substitutedwith one or more, and preferably one or two, moieties either on the samering or on different rings chosen from the groups consisting of halogen,hydroxy, protected hydroxy, cyano, nitro, C₁ to C₆ alkyl, C₁ to C₇alkoxy, C₁ to C₇ acyl, C₁ to C₇ acyloxy, carboxy, protected carboxy,carboxymethyl, protected carboxymethyl, hydroxymethyl, protectedhydroxymethyl, amino, protected amino, (monosubstituted)amino, protected(monosubstituted)amino, (disubstituted)amino, carboxamide, protectedcarboxamide, N-(C₁ to C₆ alkyl)carboxamide, protected N-(C₁ to C₆alkyl)carboxamide, N, N-di(C₁ to C₆ alkyl)carboxamide, trifluoromethyl,N-((C₁ to C₆ alkyl)sulfonyl)amino or N-(phenylsulfonyl)amino.

Examples of substituted naphthyl include a mono or di(halo)naphthylgroup such as 1, 2, 3, 4, 5, 6, 7 or 8-chloronaphthyl, 2,6-dichloronaphthyl, 2, 5-dichloronaphthyl, 3, 4-dichloronaphthyl, 1, 2,3, 4, 5, 6, 7 or 8-bromonaphthyl, 3, 4-dibromonaphthyl,3-chloro-4-fluoronaphthyl, 1, 2, 3, 4, 5, 6, 7 or 8-fluoronaphthyl andthe like; a mono or di(hydroxy)naphthyl group such as 1, 2, 3, 4, 5, 6,7 or 8-hydroxynaphthyl, 2, 4-dihydroxynaphthyl, the protected-hydroxyderivatives thereof and the like; a nitronaphthyl group such as 3- or4-nitronaphthyl; a cyanonaphthyl group, for example, 1, 2, 3, 4, 5, 6, 7or 8-cyanonaphthyl; a mono- or di(alkyl)naphthyl group such as 2, 3, 4,5, 6, 7 or 8-methylnaphthyl, 1, 2, 4-dimiethylnaphthyl, 1, 2, 3, 4, 5,6, 7 or 8-(isopropyl)naphthyl, 1, 2, 3, 4, 5, 6, 7 or 8-ethylnaphthyl,1, 2, 3, 4, 5, 6, 7 or 8-(n-propyl)naphthyl and the like; a mono ordi(alkoxy)naphthyl group, for example, 2, 6-dimethoxynaphthyl, 1, 2, 3,4, 5, 6, 7 or 8-methoxynaphthyl, 1, 2, 3, 4, 5, 6, 7 or8-ethoxynaphthyl, 1, 2, 3, 4, 5, 6, 7 or 8-(isopropoxy)naphthyl, 1, 2,3, 4, 5, 6, 7 or 8-(t-butoxy)naphthyl, 3-ethoxy-4-methoxynaphthyl andthe like; 1, 2, 3, 4, 5, 6, 7 or 8-trifluoromethylnaphthyl; a mono- ordicarboxynaphthyl or (protected carboxy)naphthyl group such as 1, 2, 3,4, 5, 6, 7 or 8-carboxynaphthyl or 2, 4-di(-protected carboxy)naphthyl;a mono-or di(hydroxymethyl)naphthyl or (protected hydroxymethyl)naphthylsuch as 1, 2, 3, 4, 5, 6, 7 or 8-(protected hydroxymethyl)naphthyl or 3,4-di(hydroxymethyl)naphthyl; a mono- or di(amino)naphthyl or (protectedamino)naphthyl such as 1, 2, 3, 4, 5, 6, 7 or 8-(amino)naphthyl or 2,4-(protected amino)-naphthyl, a mono- or di(aminomethyl)naphthyl or(protected aminomethyl)naphthyl such as 2, 3, or 4-(aminomethyl)naphthylor 2, 4-(protected aminomethyl)-naphthyl; or a mono- ordi-(N-methylsulfonylamino) naphthyl such as 1, 2, 3, 4, 5, 6, 7 or8-(N-methylsulfonylamino)naphthyl.

Also, the term "substituted naphthyl" represents disubstituted naphthylgroups wherein the substituents are different, for example,3-methyl-4-hydroxynaphth-1-yl, 3-chloro-4-hydroxynaphth-2-yl,2-methoxy-4-bromonaphth-1-yl, 4-ethyl-2-hydroxynaphth-1-yl,3-hydroxy-4-nitronaphth-2-yl, 2-hydroxy-4-chloronaphth-1-yl,2-methoxy-7-bromonaphth-1-yl, 4-ethyl-5-hydroxynaphth-2-yl,3-hydroxy-8-nitronaphth-2-yl, 2-hydroxy-5-chloronaphth-1-yl and thelike.

The terms "halo" and "halogen" refer to the fluoro, chloro, bromo oriodo groups. There can be one or more halogen, which are the same ordifferent. Preferred halogens are chloro and fluoro.

The term "(monosubstituted)amino" refers to an amino group with onesubstituent chosen from the group consisting of phenyl, substitutedphenyl, C₁ to C₆ alkyl, C₁ to C₆ substituted alkyl, C₁ to C₇ acyl, C₂ toC₇ alkenyl, C₂ to C₇ substituted alkenyl, C₂ to C₇ alkynyl, C₂ to C₇substituted alkynyl, C₇ to C₁₂ phenylalkyl, C₇ to C₁₂ substitutedphenylalkyl and heterocyclic ring. The (monosubstituted)amino canadditionally have an amino-protecting group as encompassed by the term"protected (monosubstituted)amino."

The term "(disubstituted)amino" refers to amino groups with twosubstituents chosen from the group consisting of phenyl, substitutedphenyl, C₁ to C₆ alkyl, C₁ to C₆ substituted alkyl, C₁ to C₇ acyl, C₂ toC₇ alkenyl, C₂ to C₇ alkynyl, C₇ to C₁₂ phenylalkyl, and C₇ to C₁₂substituted phenylalkyl. The two substituents can be the same ordifferent.

The term "amino-protecting group" as used herein refers to substituentsof the amino group commonly employed to block or protect the aminofunctionality while reacting other functional groups of the molecule.The term "protected (monosubstituted)amino" means there is anamino-protecting group on the monosubstituted amino nitrogen atom. Inaddition, the term "protected carboxamide" means there is anamino-protecting group on the carboxamide nitrogen.

Examples of such amino-protecting groups include the formyl ("For")group, the trityl group, the phthalimido group, the trichloroacetylgroup, the chloroacetyl, bromoacetyl, and iodoacetyl groups,urethane-type blocking groups, such as t-butoxycarbonyl ("Boc"),2-(4-biphenylyl)propyl-2-oxycarbonyl ("Bpoc"),2-phenylpropyl-2-oxycarbonyl ("Poc"), 2-(4-xenyl)isopropoxycarbonyl,1,1-diphenylethyl-1-oxycarbonyl, 1,1-diphenylpropyl-1-oxycarbonyl,2-(3,5-dimethoxyphenyl)propyl-2-oxycarbonyl ("Ddz"),2-(p-toluyl)propyl-2-oxycarbonyl, cyclopentanyloxycarbonyl,1-methylcyclopentanyloxycarbonyl, cyclohexanyloxy-carbonyl,1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl,2-(4-toluylsulfonyl)-ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl,2-(triphenylphosphino)-ethoxycarbonyl, 9-fluorenylmethoxycarbonyl("Fmoc"), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyl-oxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, isobornyloxycarbonyl,1-piperidyloxycarbonyl, benzyloxycarbonyl ("Cbz"),4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl,α-2,4,5,-tetramethylbenzyloxycarbonyl ("Tmz"),4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl,4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl,2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyl-oxycarbonyl,4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl,4-(decyloxy)benzyloxycarbonyl and the like; the benzoylmethylsulfonylgroup, dithiasuccinoyl ("Dts"), the 2-(nitro)phenylsulfenyl group("Nps"), the diphenyl-phosphine oxide group and like amino-protectinggroups. The species of amino-protecting group employed is not criticalso long as the derivatized amino group is stable to the conditions ofthe subsequent reaction(s) and can be removed at the appropriate pointwithout disrupting the remainder of the compounds. Preferredamino-protecting groups are Boc, Cbz and Fmoc. Further examples ofamino-protecting groups embraced by the above term are well known inorganic synthesis and the peptide art and are described by, for example,T. W. Greene and P. G. M. Wuts, "Protective Groups in OrganicSynthesis," 2nd ed., John Wiley and Sons, New York, N.Y., 1991, Chapter7, M. Bodanzsky, "Principles of Peptide Synthesis," 1st and 2nd reviseded., Springer-Verlag, New York, N.Y., 1984 and 1993, and Stewart andYoung, "Solid Phase Peptide Synthesis," 2nd ed., Pierce Chemical Co.,Rockford, Ill., 1984, each of which is incorporated herein by reference.The related term "protected amino" defines an amino group substitutedwith an amino-protecting group discussed above.

The term "carboxy-protecting group" as used herein refers to one of theester derivatives of the carboxylic acid group commonly employed toblock or protect the carboxylic acid group while reactions are carriedout on other functional groups on the compound. Examples of suchcarboxylic acid protecting groups include t-butyl, 4-nitrobenzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl,2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl,3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxytrityl,4,4',4"-trimethoxytrityl, 2-phenylpropyl, trimethylsilyl,t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl,β-(trimethylsilyl)ethyl, β-(di(n-butyl)methylsilyl)ethyl,p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl,1-(trimethylsilylmethyl)propenyl and like moieties. The species ofcarboxy-protecting group employed is not critical so long as thederivatized carboxylic acid is stable to the conditions of subsequentreaction(s) and can be removed at the appropriate point withoutdisrupting the remainder of the molecule. Further examples of thesegroups are found in E. Haslam, "Protective Groups in Organic Chemistry,"J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, andT. W. Greene and P. G. M. Wuts, "Protective Groups in OrganicSynthesis," 2nd ed., John Wiley and Sons, New York, N.Y., 1991, Chapter5, each of which is incorporated herein by reference. A related term is"protected carboxy," which refers to a carboxy group substituted withone of the above carboxy-protecting groups.

The term "hydroxy-protecting group" refers to readily cleavable groupsbonded to hydroxyl groups, such as the tetrahydropyranyl,2-methoxypropyl, 1-ethoxyethyl, methoxymethyl, 2-methoxyethoxymethyl,methylthiomethyl, t-butyl, t-amyl, trityl, 4-methoxytrityl,4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, benzyl, allyl,trimethylsilyl, (t-butyl)dimethylsilyl, 2,2,2-trichloroethoxycarbonylgroups and the like. The species of hydroxy-protecting group is notcritical so long as the derivatized hydroxyl group is stable to theconditions of subsequent reaction(s) and can be removed at theappropriate point without disrupting the remainder of the molecule.Further examples of hydroxy-protecting groups are described by C. B.Reese and E. Haslam, "Protective Groups in Organic Chemistry," J. G. W.McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapters 3 and 4,respectively, and T. W. Greene and P. G. M. Wuts, "Protective Groups inOrganic Synthesis," 2nd ed., John Wiley and Sons, New York, N.Y., 1991,Chapters 2 and 3. Related terms are "protected hydroxy," and "protectedhydoxymethyl" which refer to a hydroxy or hydroxymethyl substituted withone of the above hydroxy-protecting groups.

The substituent term "C₁ to C₄ alkylthio" refers to sulfide groups suchas methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio,t-butylthio and like groups.

The substituent term "C₁ to C₄ alkylsulfoxide" indicates sulfoxidegroups such as methylsulfoxide, ethylsulfoxide, n-propylsulfoxide,isopropylsulfoxide, n-butylsulfoxide, sec-butylsulfoxide and the like.

The term "C₁ to C₄ alkylsulfonyl" encompasses groups such asmethylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl,n-butylsulfonyl, t-butylsulfonyl and the like.

The terms "C₁ to C₄ substituted alkylthio," "C₁ to C₄ substitutedalkylsulfoxide," and "C₁ to C₄ substituted alkylsulfonyl," denote the C₁to C₄ alkyl portion of these groups may be substituted as describedabove in relation to "substituted alkyl."

The terms "phenylthio,"phenylsulfoxide," and "phenylsulfonyl" specify athiol, a sulfoxide, or sulfone, respectively, containing a phenyl group.

The terms "substituted phenylthio," "substituted phenylsulfoxide," and"substituted phenylsulfonyl" mean that the phenyl of these groups can besubstituted as described above in relation to "substituted phenyl."

The term "C₁ to C₆ alkylaminocarbonyl" means a C₁ to C₆ alkyl attachedto an aminocarbonyl group, where the C₁ to C₆ alkylaminocarbonyl groupsare the resulting urea when an isocyanate is used in the reactionscheme. Examples of C₁ to C₆ alkylaminocarbonyl includemethylaminocarbonyl (from methylisocyanate), ethylaminocarbonyl (fromethylisocyanate), propylaminocarbonyl (from propylisocyanate),butylaminocarbonyl (from butylisocyatate). The term "C₁ to C₆substituted alkylaminocarbonyl" denotes a substituted alkyl bonded to anaminocarbonyl group, which alkyl may be substituted as described abovein relation to C₁ to C₆ substituted alkyl. Examples of C₁ to C₆substituted alkylaminocarbonyl include, for example,methoxymethylaminocarbonyl (from methoxymethylisocyanate),2-chloroethylaminocarbonyl (from 2-chloroethylisocyanate),2-oxopropylaminocarbonyl (from 2-oxopropylisocyanate), and4-phenylbutylaminocarbonyl (from phenylbutylisocyanate).

The term "phenylaminocarbonyl" means a phenyl attached to anaminocarbonyl group, where the phenylaminocarbonyl groups are the resultof using a phenylisocyanate in the reaction scheme. The term"substituted phenylaminocarbonyl" denotes a substituted phenyl bonded toan aminocarbonyl group, which phenyl may be substituted as describedabove in relation to substituted phenyl. Examples of substitutedphenylaminocarbonyl include 2-chlorophenylaminocarbonyl (from2-chlorophenylisocyanate), 3-chlorophenylaminocarbonyl (from3-chlorophenylisocyanate), 2-nitorphenylaminocarbonyl (from2-nitrophenylisocyanate), 4-biphenylaminocarbonyl (from4-biphenylisocyanate), and 4-methoxyphenylaminocarbonyl (from4-methoxyphenylisocyanate).

The substituent terms "cyclic C₂ to C₇ alkylene," "substituted cyclic C₂to C₇ alkylene," "cyclic C₂ to C₇ heteroalkylene," and "substitutedcyclic C₂ to C₇ heteroalkylene," define such a cyclic group bonded("fused") to the phenyl radical resulting in a bicyclic ring system. Thecyclic group may be saturated or contain one or two double bonds.Furthermore, the cyclic group may have one or two methylene or methinegroups replaced by one or two oxygen, nitrogen or sulfur atoms which arethe cyclic C₂ to C₇ heteroalkylene.

The cyclic alkylene or heteroalkylene group may be substituted once ortwice by the same or different substituents selected from the groupconsisting of the following moieties: hydroxy, protected hydroxy,carboxy, protected carboxy, oxo, protected oxo, C₁ to C₄ acyloxy,formyl, C₁ to C₇ acyl, C₁ to C₆ alkyl, C₁ to C₇ alkoxy, C₁ to C₄alkylthio, C₁ to C₄ alkylsulfoxide, C₁ to C₄ alkylsulfonyl, halo, amino,protected amino, (monosubstituted)amino, protected(monosubstituted)amino, (disubstituted)amino, hydroxymethyl and aprotected hydroxymethyl.

The cyclic alkylene or heteroalkylene group fused onto the benzeneradical can contain two to ten ring members, but it preferably containsthree to six members. Examples of such saturated cyclic groups are whenthe resultant bicyclic ring system is 2,3-dihydro-indanyl and a tetralinring. When the cyclic groups are unsaturated, examples occur when theresultant bicyclic ring system is a naphthyl ring or indolyl. Examplesof fused cyclic groups which each contain one nitrogen atom and one ormore double bond, preferably one or two double bonds, are when thephenyl is fused to a pyridino, pyrano, pyrrolo, pyridinyl,dihydropyrrolo, or dihydropyridinyl ring. Examples of fused cyclicgroups which each contain one oxygen atom and one or two double bondsare when the phenyl ring is fused to a furo, pyrano, dihydrofurano, ordihydropyrano ring. Examples of fused cyclic groups which each have onesulfur atom and contain one or two double bonds are when the phenyl isfused to a thieno, thiopyrano, dihydrothieno or dihydrothiopyrano ring.Examples of cyclic groups which contain two heteroatoms selected fromsulfur and nitrogen and one or two double bonds are when the phenyl ringis fused to a thiazolo, isothiazolo, dihydrothiazolo ordihydroisothiazolo ring. Examples of cyclic groups which contain twoheteroatoms selected from oxygen and nitrogen and one or two doublebonds are when the benzene ring is fused to an oxazolo, isoxazolo,dihydrooxazolo or dihydroisoxazolo ring. Examples of cyclic groups whichcontain two nitrogen heteroatoms and one or two double bonds occur whenthe benzene ring is fused to a pyrazolo, imidazolo, dihydropyrazolo ordihydroimidazolo ring or pyrazinyl.

One or more of the tricyclic tetrahydroquinoline derivatives, evenwithin a given library, may be present as a salt. The term "salt"encompasses those salts that form with the carboxylate anions and aminenitrogens and include salts formed with the organic and inorganic anionsand cations discussed below. Furthermore, the term includes salts thatform by standard acid-base reactions with basic groups (such as aminogroups) and organic or inorganic acids. Such acids include hydrochloric,sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric,palmitic, cholic, pamoic, mucic, D-glutamic, D-camphoric, glutaric,phthalic, tartaric, lauric, stearic, salicyclic, methanesulfonic,benzenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids.

The term "organic or inorganic cation" refers to counterions for thecarboxylate anion of a carboxylate salt. The counter-ions are chosenfrom the alkali and alkaline earth metals, (such as lithium, sodium,potassium, barium, aluminum and calcium); ammonium and mono-, di- andtri-alkyl amines such as trimethylamine, cyclohexylamine; and theorganic cations, such as dibenzylammonium, benzylammonium,2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium,phenylethylbenzylammonium, dibenzylethylenediammonium, and like cations.See, for example, "Pharmaceutical Salts," Berge et al., J. Pharm .Sci.,66:1-19 (1977), which is incorporated herein by reference. Other cationsencompassed by the above term include the protonated form of procaine,quinine and N-methylglucosamine, and the protonated forms of basic aminoacids such as glycine, omithine, histidine, phenylglycine, lysine andarginine. Furthermore, any zwitterionic form of the instant compoundsformed by a carboxylic acid and an amino group is referred to by thisterm. For example, a cation for a carboxylate anion will exist when R₂or R₃ is substituted with a (quaternary ammonium)methyl group. Apreferred cation for the carboxylate anion is the sodium cation.

The compounds of the above Formulae can also exist as solvates andhydrates. Thus, these compounds may crystallize with, for example,waters of hydration, or one, a number of, or any fraction thereof ofmolecules of the mother liquor solvent. The solvates and hydrates ofsuch compounds are included within the scope of this invention.

One or more tricyclic tetrahydroquinoline derivatives, even when in alibrary, can be in the biologically active ester form, such as thenon-toxic, metabolically-labile ester-form. Such ester forms induceincreased blood levels and prolong the efficacy of the correspondingnon-esterified forms of the compounds. Ester groups which can be usedinclude the lower alkoxymethyl groups, for example, methoxymethyl,ethoxymethyl, isopropoxymethyl and the like; the α-(C₁ to C₇)alkoxyethyl groups, for example methoxyethyl, ethoxyethyl, propoxyethyl,isopropoxyethyl and the like; the 2-oxo-1,3-diooxlen-4-ylmethyl groups,such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl,5-phenyl-2-oxo-1,3-dioxolen-4-ylmethyl and the like; the C₁ to C₄alkylthiomethyl groups, for example methylthiomethyl, ethylthiomethyl,iso-propylthiomethyl and the like; the acyloxymethyl groups, for examplepivaloyloxymethyl, pivaloyloxyethyl, a-acetoxymethyl and the like; theethoxycarbonyl-1-methyl group; the a-acetoxyethyl; the 1-(C₁ to C₇alkyloxycarbonyloxy)ethyl groups such as the 1-(ethoxycarbonyloxy)ethylgroup; and the 1-(C₁ to C₇ alkylaminocarbonyloxy)ethyl groups such asthe 1-(methylaminocarbonyloxy)ethyl group.

The term "amino acid" includes any one of the twenty naturally-occurringamino acids or the D-form of any one of the naturally-occurring aminoacids. In addition, the term "amino acid" also includes othernon-naturally occurring amino acids besides the D-amino acids, which arefunctional equivalents of the naturally-occurring amino acids. Suchnon-naturally-occurring amino acids include, for example, norleucine("Nle"), norvaline ("Nva"), β-Alanine, L- or D-naphthalanine, ornithine("Om"), homoarginine (homoArg) and others well known in the peptide art,such as those described in M. Bodanzsky, "Principles of PeptideSynthesis," 1st and 2nd revised ed., Springer-Verlag, New York, N.Y.,1984 and 1993, and Stewart and Young, "Solid Phase Peptide Synthesis,"2nd ed., Pierce Chemical Co., Rockford, Ill., 1984, both of which areincorporated herein by reference. Amino acids and amino acid analogs canbe purchased commercially (Sigma Chemical Co.; Advanced Chemtech) orsynthesized using methods known in the art.

The amino acids are indicated herein by either their full name or by thecommonly known three letter code. Further, in the naming of amino acids,"D-" or "d-" designates an amino acid having the "D" configuration, asopposed to the naturally occurring L-amino acids. Where no specificconfiguration is indicated, one skilled in the art would understand theamino acid to be an L-amino acid. The amino acids can, however, also bein racemic mixtures of the D- and L-configuration or the D-amino acidcan readily be substituted for that in the L-configuration.

As used herein, a chemical or combinatorial "library" is anintentionally created collection of differing molecules which can beprepared by the synthetic means provided below or otherwise and screenedfor biological activity in a variety of formats (e.g., libraries ofsoluble molecules, libraries of compounds attached to resin beads,silica chips or other solid supports). The libraries can be screened inany variety of assays, such as those detailed below as well as othersuseful for assessing the biological activity. The libraries are usefulin their ability to rapidly synthesize and screen a diverse number orcompounds. Moreover, the libraries will generally have at least oneactive compound and are generally prepared in such that the compoundsare in equimolar quantities.

"Combinatorial chemistry" or "combinatorial synthesis" refers to theparallel synthesis of diverse compounds by sequential addition ofreagents which leads to the generation of large chemical librarieshaving molecular diversity. Combinatorial chemistry, therefore, involvesthe systematic and repetitive, covalent connection of a set of different"building blocks" of varying structures to yield large arrays of diversemolecular entities.

The compounds of Formula I and combinatorial libraries containing thesame can be prepared as set forth in the Reaction Schemes provided inthe Figures and described below. The substituents R¹ to R⁸ in theReaction Schemes have the same meaning as those described above. Thesubstituent Y in the Reaction Schemes is the same as defined above withthe exception that it is still bound to resin or is the functionalizedresin and, therefore, has one less hydrogen.

In brief, the tricyclic tetrahydroquinoline compounds of the presentinvention can be prepared according to Reaction Scheme I as shown inFIG. 1. As depicted in FIG. 1, a solid support resin-bound aniline(resin identified by a shaded circle) is reacted, in situ, with analdehyde and is thereby, converted to the corresponding imine. This isperformed in the presence of a dieneophile and an acid. In the presenceof the dieneophile, the imine undergoes a hetero-Diels-Alder reactionand yields the tetrahydroquinoline.

More specifically, as shown by Reaction Scheme II in FIG. 2, and asprovided in Example 1, the tricyclic tetrahydroquinolines and librariescontaining the same are prepared by the following more detailed steps.First, the anilines, (as shown in FIG. 2), are coupled to resin, such asMBHA (FIG. 2), MBA, Tentagel™ and the like as described below, using acarbodiimide coupling agent, such as dicyclohexylcarbodiimide,diisopropylcarbodiimide, N-dimethylaminoethyl-N'-ethyl-carbodiimide andthe like, and an activator, such as 1-hydroxybenzotriazole,7-aza-1-hydroxybenzotriazole and the like, in an aprotic polar solventsuch as dichloromethane, dimethylformamide and the like, at between 10°C. and 100° C., preferably at 25° C., for 2 to 24 hours, preferably 8 to16 hours. The amino protecting group ("PG"), where necessary and used,is removed following standard procedures and the free amino group of theindividual or mixtures of resin-bound anilines is condensed with analdehyde in the presence of a dieneophile, such as cyclopentadiene,cyclohexadiene and the like and in the presence of an acid, such astrifluoroacetic acid, toluenesulfonic acid and the like, using in apolar solvent, such as dichloromethane, dimethylformamide,dimethylacetamide, N-methylpyrrolidinone or the like, for a period of 1to 72 hours, usually 12 to 24 hours at 20° C. to 75 ° C. and preferablyat 25 ° C. to arrive at novel tricyclic tetrahydroquinoline derivatives.Where the dieneophile is regiochemically stable, such as cycloheadiene,it would be appreciated by those of skill in the art that it can besubstituted without departing from the spirit of the invention. Suchregiochemically stable dieneophiles can be substituted with, forexample, C₁ to C₁₀ alkyl, C₁ to C₇ alkoxy, or C₁ to C₇ acyloxy. Finally,the compounds can be cleaved from the resin by the methods common tothose skilled in the art and the compounds tested for biologicalactivity.

More specifically, as shown by Reaction Scheme III in FIG. 3, thebranched tricyclic tetrahydroquinolines and libraries containing thesame are prepared by the following more detailed steps. First, as shownin FIG. 3, N-Boc-nitrophenylalanines or, alternatively, the FMOCprotected analogs are coupled to resin, such as MBHA, MBA, Tentage™ andthe like as described below, using a carbodiimide coupling agent, suchas dicyclohexylcarbodiimide,diisopropyl-carbodiimide,N-dimethylaminoethyl-N'-ethyl-carbodiimide andthe like, and an activator, such as 1-hydroxybenzotriazole,7-aza-1-hydroxybenzotriazole and the like, in an aprotic polar solventsuch as dichloromethane, dimethylformamide and the like, at between 10°C. and 100° C., preferably at 25° C., for 2 to 24 hours, preferably 8 to16 hours. The BOC of the α-amino group is removed using a strong acidsuch as trifluoroacetic acid or trifluoromethanesulfonic acid and thelike (1-95%) in an aprotic solvent such as dichloromethane,dimethylformamide and the like, at between 10° C. and 100° C.,preferably at 25° C., for 2 to 24 hours, preferably 8 to 16 hours.Alternatively, the FMOC of the α amino acid is removed using an aminebase such as piperidine, pyrrolidine, or morpholine and the like (1-95%)in an aprotic solvent such as dichloromethane, dimethylformamide and thelike, at between 10° C. and 100° C., preferably at 25° C., for 2 to 24hours, preferably 8 to 16 hours. The free amino group is coupled to acarboxylic acid, such as acetic acid, benzoic acid and the like (FIG.3), using a carbodiimide coupling agent, such asdicyclohexylcarbodiimide, diisopropyl-carbodiimide,N-dimethylaminoethyl-N'-ethyl-carbodiimide and the like, and anactivator, such as 1-hydroxybenzotriazole, 7-aza-1-hydroxybenzotriazoleand the like, in an aprotic polar solvent such as dichloromethane,dimethylformamide and the like, at between 10° C. and 100° C.,preferably at 25° C., for 2 to 24 hours, preferably 8 to 16 hours. Thenitro group of the phenylalanine is subjected to conditions to reducethe nitro group to an amine, in the case of Reaction Scheme III tindichloride, in an aprotic solvent such as chloroform, dimethylformamide,dimethylacetamide, N-methylpyrrolidinone for 2 to 36 hours andpreferably 16 hours at 20° C. to 125° C., preferably at 25-30° C. Thefree amino group of the individual or mixtures of resin-boundaminophenylalanines is condensed with an aldehyde in the presence of adieneophile, such as cyclopentadiene, cyclohexadiene and the like, andan acid such as trifluoroacetic acid or toluenesulfonic acid and thelike, using in a polar solvent, such as dichloromethane,dimethylformamide, dimethylacetamide, N-methylpyrrolidinone or the like,for a period of 1 to 72 hours, usually 12 to 24 hours at 20° C. to 75°C. and preferably at 25° C. to arrive at novel ttricyclictetrahydroquinolinederivatives. Finally, the compounds can be cleavedfrom the resin by the methods common to those skilled in the art and thecompounds tested for biological activity. It should be appreciated bythose of skill in the art that with certain resins, cleavage from theresin results in the functional group on the resin coming off the resinand being maintained with the cleaved compounds. For example, with anamino-resin, such as methylbenzhydrylamine resin, the amine group fromthe resin is cleaved off the resin and makes the tricyclictetrahydroquinoline(s) of interest an amide.

The term "functionalized resin" means any resin where functional groupshave been introduced into the resin, as is common in the art. Suchresins include, for example, those functionalized with amino, amide, orhydroxy groups. Such resins which can serve as solid supports are wellknown in the art and include, for example,4-methylbenzhydrylamine-copoly(styrene-1% divinylbenzene) (MBHA),4-hydroxymethylphenoxymethyl-copoly(styrene-1% divinylbenzene),4-oxymethyl-phenyl-acetamido-copoly(styrene-1% divinylbenzene)(Wang),4-(oxymethyl)phenylacetamido methyl (Pam), and Tentage™, from RappPolymere Gmbh, trialkoxy-diphenyl-methyl ester-copoly-(styrene-1%divinylbenzene)(RINK) all of which are commercially available.

Preparation of the combinatorial libraries can be by the "split resinapproach." The split resin approach is described by, for example, U.S.Pat. No. 5,010,175 to Rutter, WO PCT 91/19735 to Simon, and Gallop etal., J. Med. Chem., 37:1233-1251 (1994), all of which are incorporatedherein by reference.

Exemplary amino carboxylic acids which can be used in the above ReactionSchemes include 2, 3, and 4-aminobenzoic acid, aminohippuric acid,4'-aminophenylalanine, 4'-nitrophenylalanine, anthranilic acid(2-aminobenzoic acid), 2-amino-4-chlorobenzoic acid,2-amino-4-fluorobenzoic acid, 4-nitroanthranilic acid,2-amino-5-bromobenzoic acid, 2-amino-5-chlorobenzoic acid,2-amino-5-fluorobenzoic acid, 2-amino-5-iodobenzoic acid,2-amino-5-methylbenzoic acid, 2-amino-6-methylbenzoic acid,4,5-difluoroanthranilic acid, 3-amino-2-naphthoic acid, 4-aminobenzoicacid, 4-amino-2-chlorobenzoic acid, 4-amino-2-hydroxybenzoic acid,4-amino-3-hydroxybenzoic acid, 4-amino-3-methoxybenzoic acid, and4-amino-3-methylbenzoic acid. Additional amino benzoic acids oraminoaryl carboxylic acids are provided in the ensuing Examples.

Exemplary aldehydes which can be used in the above reaction schemes Iand II are glyoxylic acid, 1-napthaldehyde, 2,3,4-trifluorobenzaldehyde,2,3 ,5-trichlorobenzaldehyde, 2,3-difluorobenzaldehyde,2,4-dichlorobenzaldehyde, 2,5-difluorobenzaldehyde,2,5-dimethylbenzaldehyde, 2,6-difluorobenzaldehyde, 2-bromobenzaldehyde,2-chloro-5-nitrobenzaldehyde, 2-fluorobenzaldehyde,3,4-(methylenedioxy)-6-nitrobenzaldehyde, 3,4-difluorobenzaldehyde,3,5-bis(trifluoromethyl)benzaldehyde, 3,5-dichlorobenzaldehyde,3-cyanobenzaldehyde, 3-fluorobenzaldehyde, 3-formylchromone,3-nitro-4-chlorobenzaldehyde, 3-phenoxybenzaldehyde,4-cyanobenzaldehyde, 4-pyridinecarboxaldehyde,3-methoxy-2-nitro-benzaldehyde, 3-hydroxy-4-nitro-benzaldehyde.Additional aldehydes include the following: 2-nitrobenzaldehyde, 2,4-dinitrobenzaldehyde, 4-methyl-2-nitrobenzaldehyde,4,5-methylenedioxy-2-nitrobenzaldehyde, 5-ethyl-2-nitrobenzaldehyde,4,5-dimethoxy-2-nitrobenzaldehyde, 5-chloro-2-nitrobenzaldehyde,3-fluoro-2-nitrobenzaldehyde, 3-trifluoro-2-nitrobenzaldehyde,4-(dimethylamino)-2-nitrobenzaldehyde, 3-methoxy-2-nitrobenzaldehyde,5-hydroxy-2-nitrobenzaldehyde, 2,6-dinitrobenzaldehyde and the like.

Exemplary carboxylic acids which can be used in the above ReactionSchemes include, but are not limited to, acetic acid, butyric acid,cyclobutanecarboxylic acid, cycloheptanecarboxylic acid,cyclohexanebutyric acid, cyclohexanecarboxylic acid,cyclohexanepropionic acid, cyclohexylacetic acid, cyclopentanecarboxylicacid, cyclopentylacetic acid, hydrocinnamic acid, isobutyric acid,isovaleric acid, octanoic acid, propionic acid, tert-butylacetic acid,trimethylacetic acid, 1-adamantaneacetic acid,4-methyl-1-cyclohexanecarboxylic acid, 4-methylcyclohexaneacetic acid,4-methylvaleric acid, 2-ethyl-2-hexenoic acid, 2-ethylbutyric acid,2-ethylhexanoic acid, 2-methylbutyric acid,2-methylcyclopropanecarboxylic acid, 2-norbornaneacetic acid,2-phenylbutyric acid, 2-propylpentanoic acid, 3,3,3-triphenylpropionicacid, 3,3-diphenylpropionic acid, 4-tert-butyl-cyclohexanecarboxylicacid, 3,5,5-trimethylhexanoic acid, 5-phenylvaleric acid,3-(2-methoxyphenyl)propionic acid, 3-(3,4,5-trimethoxyphenyl)propionicacid, 3-(3,4-dimethoxyphenyl)propionic acid, heptanoic acid,3-cyclopentylpropionic acid, formic acid, lauric acid, 3-methylvalericacid, 3-phenylbutyric acid, α-cyclohexylphenylacetic acid,α-methylcinnamic acid, crotonic acid, ethoxyacetic acid,4-chlorocinnamic acid, 4-ethoxyphenylacetic acid, m-tolylacetic acid,methoxyacetic acid, p-tolylacetic acid, phenoxyacetic acid, phenylaceticacid, tiglic acid, trans-3-hexenoic acid, trans-cinnamic acid,trans-styrylacetic acid, triphenylacetic acid, 4-fluorophenylaceticacid, vinylacetic acid, (2,5-dimethoxyphenyl)acetic acid,(2-naphthoxy)acetic acid, (3,4-dimethoxyphenyl)acetic acid,(α-α-α-trifluoro-m-tolyl)acetic acid, (methylthio)acetic acid,1-(4-chlorophenyl)-1-cyclopentanecarboxylic acid, 1-naphthylacetic acid,1-phenyl-1-cyclopropanecarboxylic acid, 4-isobutyl-α-methylphenylaceticacid, 4-methoxyphenylacetic acid, 2,4-hexadienoic acid,2-(trifluoromethyl)-cinnamic acid, 2-chloro-4-fluorophenylacetic acid,2-naphthylacetic acid, 99%, 3,4,5-trimethoxycinnamic acid,3,4-dichlorophenylacetic acid, 3,4-dimethylbenzoic acid,3,4,5-trimethoxyphenylacetic acid, 3-benzoylpropionic acid,3-bromophenylacetic acid, 3-fluorophenylacetic acid,3-methoxyphenylacetic acid, 3-thiopheneacetic acid, 4-biphenylaceticacid, 4-bromophenylacetic acid, α,α,α-trifluoro-m-toluic acid,α,α,a-trifluoro-o-toluic acid, benzoic acid, niflumic acid, o-anisicacid, o-toluic acid, piperonylic acid, 1-napthoic acid,2,3-dichlorobenzoic acid, 2,3-dimethoxybenzoic acid, 2,4-dichlorobenzoicacid, 2,4-difluorobenzoic acid, 2,4-dimethoxybenzoic acid,2,4-dimethylbenzoic acid, 2,5-dichlorobenzoic acid, 2,5-dimethylbenzoicacid, 2,6-dichlorobenzoic acid, 2,6-difluorobenzoic acid,2,6-dimethoxybenzoic acid, 2-bromobenzoic acid,2-chloro-4,5-difluorobenzoic acid, 2-chlorobenzoic acid, 2-ethoxybenzoicacid, 2-fluorobenzoic acid, 2-napthoic acid, 3,4,5-triethoxybenzoicacid, 3,4,5-trimethoxybenzoic acid, 3,4-dichlorobenzoic acid,3,4-difluorobenzoic acid, 3,4-dimethoxybenzoic acid,3,5-bis(trifluoromethyl)-benzoic acid, 5-bromo-2-chlorobenzoic acid,3,5-dimethyl-p-anisic acid, 3-bromobenzoic acid, 3-chlorobenzoic acid,3-cyanobenzoic acid, 3-dimethylaminobenzoic acid,3-fluoro-4-methylbenzoic acid, 3-fluorobenzoic acid,3-iodo-4-methylbenzoic acid, 3-phenoxybenzoic acid, 4-chloro-o-anisicacid, α,α,α-trifluoro-p-toluic acid, 4-cyanobenzoic acid,4-dimethylaminobenzoic acid, 4-ethoxybenzoic acid, Isonicotinic acid,4-ethylbenzoic acid, m-anisic acid, m-toluic acid, nicotinic acid,p-anisic acid, p-toluic acid, picolinic acid, pyrrole-2-carboxylic acid,4-fluorobenzoic acid, 4-isopropoxybenzoic acid, tetrahydro-2-furoicacid, tetrahydro-3-furoic acid, trans-3-(3-pyridyl)acrylic acid,xanthene-9-carboxylic acid, (4-pyridylthio)acetic acid,(phenylthio)acetic acid, 4-iodobenzoic acid, 4-isopropylbenzoic acid,2-furoic acid, 2-pyrazinecarboxylic acid, 2-thiopheneacetic acid,2-thiophenecarboxylic acid, 5-bromonicotinic acid, 3,5-dichlorobenzoicacid, 6-chloronicotinic acid, 3,5-dimethoxybenzoic acid,3,5-dimethylbenzoic acid, chromone-2-carboxylic acid,1-isoquinolinecarboxylic acid, 3-methyl-2-thiophenecarboxaldehyde,4'-ethyl-4-biphenylcarboxylic acid, 4-(diethylamino)benzoic acid,4-benzoylbenzoic acid, 4-biphenylcarboxylic acid, 4-bromobenzoic acid,4-butylbenzoic acid, 4-chlorobenzoic acid, additional acids include thefollowing; acetyl chloride, phenoxyacetyl chloride,4-chlorophenoxyacetyl chloride benzyloxyacetyl chloride andacetoxyacetyl chloride.

The tricyclic tetrahydroquinolines prepared by the above ReactionSchemes, once cleaved from the resin, result in compounds of Formula II:##STR4##

These tetrahydroquinoline compounds of Formula II can be converted,generally before cleavage from the resin, to alternatively substitutedcompounds having an alkyl or acyl, or other functionality as defined R⁶above and provided by Formula I: ##STR5##

The tricyclic tetrahydroquinolines of Formula II, before cleavage fromthe resin, can be substituted at positions R⁶ following Reaction SchemeIV provided in FIG. 4. Briefly, as shown in Reaction Scheme IV, thetricyclic tetrahydroquinoline prepared by the above Reaction Schemes I,II or III (Reaction Scheme III repeated in FIG. 4) is condensed with acarboxylic acid, carboxylic acid anhydride, acid halide, alkyl halidesulfonyl halide or isocyanate in an aprotic solvent, such asdimethylformamide, dichloromethane, 1-methyl-2-pyrrolidinone,N-N,-dimethylacetamide, tetrahydrofuran, dioxane and the like, in thepresence of an acid acceptor, if desired, to furnish a substitutedtricyclic tetrahydroquinoline.

For example, preparation of the library containing alternativelysubstituted tricyclic tetrahydroquinoline other than R⁶ equal to ahydrogen atom involves, instead of cleaving from the resin, free NH ofthe newly formed tricyclic tetrahydroquinoline compound being reactedwith a carboxylic acid activated with N- (dimethylamino)-1H-1, 2,3-triazolo 4,5-b!pyridin-1-ylmethylene!-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU, PerSeptive Biosystems, Farmingham,Mass.), dissolved in dimethylformamide, N-N,-dimethylacetamide,1-methyl-2-pyrrolidinone and the like. The reaction is allowed toproceed for 1 to 24 hours at 20° C. to 80° C., preferably at 25° C. for3 to 5 hours to yield various carboxamide derivatives. Finally, thecompounds are cleaved from the resin as described above and tested forbiological activity.

Exemplary carboxylic acid, carboxylic acid anhydride, acid halide, alkylhalide or isocyanate which can be used include nalidixic acid,2-phenyl-4-quinolinecarboxylic acid, 2-pyrazinecarboxylic acid, niflumicacid, 4-nitrophenylacetic acid, 4-(-nitrophenyl)butyric acid,(3,4-dimethoxyphenyl)acetic acid, 3,4-(methylenedioxy)phenylacetic acid,4-nitrocinnamic acid, 3,4,-(methylenedioxy)cinnamic acid,3,4,5-trimethoxycinnamic acid, benzoic acid, 2-chlorobenzoic acid,2-nitrobenzoic acid, 2-(p-toluoyl)benzoic acid, 2,4-dinitrophenylaceticacid, 3-(3,4,5-trimethoxyphenyl)-proprionic acid, 4-biphenylacetic acid,1-napthylacetic acid, (2-napthoxy)acetic acid, trans-cinnamic acid,picolinic acid, 3-amino-4-hydroxybenzoic acid, (4-pyridylthio)aceticacid, 2,4-dichlorobenzoic acid, 3,4-dichlorobenzoic acid,4-biphenylcarboxylic acid, thiophenoxyacetic acid, 1-benzoylpropionicacid, phenylacetic acid, hydrocinnamic acid, 3,3-diphenylpropionic acid,3,3,3-triphenylpropionic acid, 4-phenylbutyric acid, phenoxyacetic acid,(+/-)-2-phenoxypropionic acid, 2,4-dimethoxybenzoic acid,3,4-dimethoxybenzoic acid, 3,4-dihydroxybenzoic acid,2,4-dihydroxybenzoic acid, 3,4,5-trimethoxybenzoic acid,3,4,5-triethoxybenzoic acid, 3,4,5-trihydroxybenzoyl, 2-benzoylbenzoicacid, 1-napthoic acid, xanthene-9-carboxylic acid,4-chloro-2-nitrobenzoic acid, 2-chloro-4-nitrobenzoic acid,4-chloro-3-nitrobenzoic acid, 2-chloro-5-nitrobenzoic acid,4-dimethylaminobenzoic acid, 4-(diethylamino)benzoic acid,4-nitrobenzoic acid, 3-dimethylaminobenzoic acid, p-toluic acid,p-anisic acid, trimethylacetic acid, tert-butylacetic acid,(-)-menthoxyacetic acid, cyclohexanecarboxylic acid, cyclohexylaceticacid, dicyclohexylacetic acid, cyclohexanebutyric acid,cycloheptanecarboxylic acid, abietic acid, acetic acid, octanoic acid,(methylthio)acetic acid, 3-nitropropionic acid, 4-amino-3 hydroxybenzoicacid, 2-methyl-4-nitro-1-imidizole propionic acid, 2-furoic acid,(s)(-)-2-pyrrolidone-5-carboxylic acid, (2-pyrimidylthio)acetic acid,4-methoxy-2-quinolinecarboxylic acid, 1-adamantanecarboxylic acid,piperonylic acid, 5-methyl-3-phenylisoxazole-4-carboxylic acid,rhodanine-3-acetic acid, 2-norbomaneacetic acid, nicotinnic acid,9-oxo-9H-thioxanthene-3-carboxylic acid 10,10 dioxide,2-thiophenecarboxylic acid, 5-nitro-2-furoic acid, indole-3-acetic acid,isonicotinic acid, lithocholic acid, cholic acid, deoxycholic acid,hyodeoxycholic acid, Boc-L-Ala, Boc-L-Cys(Mob), Boc-L-Asp(Bzl),Boc-L-Glu(Bzl), Boc-L-Phe, Boc-Gly, Boc-L-His(Tos), Boc-L-Ile,Boc-L-Lys(Clz), Boc-L-Leu, Boc-Met(O), Boc-L-Asn, Boc-L-Pro, Boc-L-Gln,Boc-L-Arg(Tos), Boc-L-Ser(Bzl), Boc-L-Thr(Bzl), Boc-L-Val, Boc-L-Trp,Boc-L-Tyr(Brz), Boc-D-Ala, Boc-D-Cys(Mob), Boc-D-Asp(Bzl),Boc-D-Glu(Bzl), Boc-D-Phe, Boc-D-His(Dnp), Boc-D-Ile, Boc-D-Lys(Clz),Boc-D-Leu, Boc-D-Met(O), Boc-D-Asn, Boc-D-Pro, Boc-D-Gln,Boc-D-Arg(Tos), Boc-D-Ser(Bzl), Boc-D-Thr(Bzl), Boc-D-Val,Boc-D-Trp(CHO), Boc-D-Tyr(Brz), Boc-L-Met, 2-aminobutyric acid,4-aminobutyric acid, 2-aminoisobutyric acid, L-norleucine, D-norleucine,6-aminocaproic acid, 7-aminoheptanoic acid, thioproline, L-Norvaline,D-Norvaline, α-ornithine, methionyl sulfonyl, L-naphthyalanine,D-naphthyalanine, L-phenylglycine, D-phenylglycine, β-alanine,L-cyclohexylalanine, D-cyclohexylalanine, hydroxyproline,nitrophenylalanine, dehydroproline, 1,3-propane sultone,1-propanesulfonyl chloride, 1-octanesulfonyl chloride,perfluoro-1-octanesulfonly fluoride, (+)-10-camphorsulfonyl chloride,(-)-10-camphorsulfonyl chloride, benzenesulfonly chloride,2-nitrobenzenesulfonyl chloride, p-toluenesulfonyl chloride,4-nitrobenzenesulfonyl chloride, n-acetylsulfanilyl chloride,2,5-dichlorobenzenesulfonyl chloride, 2,4-dinitrobenzenesulfonylchloride, 2-mesitylenesulfonyl chloride, 2-napthalenesulfonyl chloride,phenylisocyanate, methylisocyanate and t-butyl isocyanate. Thoseabbreviations used above for amino acids and their protecting groups areones commonly used in the field, each of which are identified, forexample, in Stewart and Young, supra.

Pharmaceutical compositions containing the new tricyclictetrahydroquinoline derivatives are also included within the scope ofthe present invention as are methods of using the compounds andcompositions.

The new tricyclic tetrahydroquinoline compounds and libraries containingthe same can be used for a variety of purposes and indications. Forexample, to evaluate whether the subject tricyclic tetrahydroquinolineshave antimicrobial activity, and, therefore, can be used to treatinfections, the ability of the compounds to inhibit bacterial growth canbe determined by methods well known in the art. An exemplary in vitroantimicrobial activity assay is described in Blondelle and Houghten,Biochemistry 30:4671-4678 (1991), which is incorporated herein byreference. In brief, Staphylococcus aureus ATCC 29213 (Rockville, Md.)is grown overnight at 37° C. in Mueller-Hinton broth, then re-inoculatedand incubated at 37° C. to reach the exponential phase of bacterialgrowth (i.e., a final bacterial suspension containing 10⁵ to 5×10⁵colony-forming units/ml). The concentration of cells is established byplating 100 μl of the culture solution using serial dilutions (e.g.,10⁻², 10⁻³ and 10⁻⁴) onto solid agar plates. In 96-well tissue cultureplates tricyclic tetrahydroquinolines, individual or in mixtures, areadded to the bacterial suspension at concentrations derived from serialtwo-fold dilutions ranging from 1500 to 2.9 μg/ml. The plates areincubated overnight at 37° C. and the growth determined at eachconcentration by OD₆₂₀ nm. The IC₅₀ (the concentration necessary toinhibit 50% of the growth of the bacteria) can then be calculated.

Additional assays can be used to test the biological activity of theinstant tricyclic tetrahydroquinoline. Such as a competitiveenzyme-linked immunoabsorbent assay and radio-receptor assays, both asdescribed in greater detail below. The latter test, the radio-receptorassay, can be selective for either the μ, δ or κ opiate receptors and istherefore an indication of tricyclic tetrahydroquinolines' analgesicproperties.

Competitive Enzyme-Linked Immunosorbent Assay (ELISA): The competitiveELISA method which can be used here is a modification of the directELISA technique described previously in Appel et al., J. Immunol.144:976-983 (1990), which is incorporated herein by reference. Itdiffers only in the MAb addition step. Briefly, multi-well microplatesare coated with the antigenic peptide (Ac-GASPYPNLSNQQT-NH₂) at aconcentration of 100 pmol/50 μl. After blocking, 25 μl of a 1.0 mg/mlsolution of each ttricyclic tetrahydroquinolinemixture of a syntheticcombinatorial library (or individual tricyclic tetrahydroquinoline) isadded, followed by MAb 125-10F3 (Appel et al., supra) (25 μl per well).The MAb is added at a fixed dilution in which the tricyclictetrahydroquinoline in solution effectively competes for MAb bindingwith the antigenic peptide adsorbed to the plate. The remaining stepsare the same as for direct ELISA. The concentration of ttricyclictetrahydroquinolinenecessary to inhibit 50% of the MAb binding to thecontrol peptide on the plate (IC₅₀) is determined by serial dilutions ofthe tricyclic tetrahydroquinoline.

Radio-Receptor Assay: Particulate membranes can be prepared using amodification of the method described in Pasternak et al., Mol.Pharmacol. 11:340-351 (1975), which is incorporated herein by reference.Rat brains frozen in liquid nitrogen can be obtained from Rockland(Gilbertsville, Pa.). The brains are thawed, the cerebella removed andthe remaining tissue weighed. Each brain is individually homogenized in40 ml Tris-HCl buffer (50 25 mM, pH 7.4, 4° C.) and centrifuged(Sorvall® RCSC SA-600: Du Pont, Wilmington, Del.) (16,000 rpm) for 10mins. The pellets are resuspended in fresh Tris-HCl buffer and incubatedat 37° C. for 40 mins. Following incubation, the suspensions arecentrifuged as before, the resulting pellets resuspended in 100 volumesof Tris buffer and the suspensions combined. Membrane suspensions areprepared and used in the same day. Protein content of the crudehomogenates generally range from 0.15-0.2 mg/ml as determined using themethod described in M.M. Bradford, M.M., Anal. Biochem. 72:248-254(1976), which is incorporated herein by reference.

Binding assays are carried out in polypropylene tubes, each tubecontaining 0.5 ml of membrane suspension. 8 nM of ³ H-D-Ala²,Me-Phe⁴,Gly-ol⁵ !enkephalin (DAMGO) (specific activity=36Ci/mmol, 160,000 cpm per tube; which can be obtained from MultiplePeptide Systems, San Diego, Calif., through NIDA drug distributionprogram 271-90-7302) and 80 μg/ml of tricyclic tetrahydroquinoline,individual or as a mixture and Tris-HCl buffer in a total volume of 0.65ml. Assay tubes are incubated for 60 mins. at 25° C. The reaction isterminated by filtration through GF-B filters on a Tomtec harvester(Orange, Conn.). The filters are subsequently washed with 6 ml ofTris-HCl buffer, 4° C. Bound radioactivity is counted on a PharmaciaBiotech Betaplate Liquid Scintillation Counter (Piscataway, N.J.) andexpressed in cpm.

To determine inter- and intra-assay variation, standard curves in which³ H-DAMGO is incubated in the presence of a range of concentrations ofunlabeled DAMGO (0.13-3900 nM) are generally included in each plate ofeach assay (a 96-well format). Competitive inhibition assays areperformed as above using serial dilutions of the ttricyclictetrahydroquinoline, individually or in mixtures. IC₅₀ values (theconcentration necessary to inhibit 50% of ³ H-DAMGO binding) are thencalculated. As opposed to this μ receptor selective assay, assaysselective for δ receptors can be carried out using ³ H!-Naltrindole (3nM, specific activity 32 Ci/mmol as radioligand or, alternatively,assays selective for κ receptors can be carried out using ³ H!-U69,593(3 nM, specific activity 62 Ci/mmol) as radioligand.

As pharmaceutical compositions for treating infections, pain, or anyother indication the tricyclic tetrahydroquinoline compounds of thepresent invention are generally in a pharmaceutical composition so as tobe administered to a subject at dosage levels of from 0.7 to 7000 mg perday, and preferably 1 to 500 mg per day, for a normal human adult ofapproximately 70 kg of body weight, this translates into a dosage offrom 0.01 to 100 mg/kg of body weight per day. The specific dosagesemployed, however, can be varied depending upon the requirements of thepatient, the severity of the condition being treated, and the activityof the compound being employed. The determination of optimum dosages fora particular situation is within the skill of the art.

For preparing pharmaceutical compositions containing compounds is of theinvention, inert, pharmaceutically acceptable carriers are used. Thepharmaceutical carrier can be either solid or liquid. Solid formpreparations include, for example, powders, tablets, dispersiblegranules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances which can also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, or tablet disintegrating agents; it can also be anencapsulating material.

In powders, the carrier is generally a finely divided solid which is ina mixture with the finely divided active component. In tablets, theactive compound is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

For preparing pharmaceutical composition in the form of suppositories, alow-melting wax such as a mixture of fatty acid glycerides and cocoabutter is first melted and the active ingredient is dispersed thereinby, for example, stirring. The molten homogeneous mixture is then pouredinto convenient-sized molds and allowed to cool and solidify.

Powders and tablets preferably contain between about 5% to about 70% byweight of the active ingredient. Suitable carriers include, for example,magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin,dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethylcellulose, a low-melting wax, cocoa butter and the like.

The pharmaceutical compositions can include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component (with or without other carriers)is surrounded by a carrier, which is thus in association with it. In asimilar manner, cachets are also included.

Tablets, powders, cachets, and capsules can be used as solid dosageforms suitable for oral administration.

Liquid pharmaceutical compositions include, for example, solutionssuitable for oral or parenteral administration, or suspensions, andemulsions suitable for oral administration. Sterile water solutions ofthe active component or sterile solutions of the active component insolvents comprising water, ethanol, or propylene glycol are examples ofliquid compositions suitable for parenteral administration.

Sterile solutions can be prepared by dissolving the active component inthe desired solvent system, and then passing the resulting solutionthrough a membrane filter to sterilize it or, alternatively, bydissolving the sterile compound in a previously sterilized solvent understerile conditions.

Aqueous solutions for oral administration can be prepared by dissolvingthe active compound in water and adding suitable flavorants, coloringagents, stabilizers, and thickening agents as desired. Aqueoussuspensions for oral use can be made by dispersing the finely dividedactive component in water together with a viscous material such asnatural or synthetic gums, resins, methyl cellulose, sodiumcarboxymethyl cellulose, and other suspending agents known to thepharmaceutical formulation art.

Preferably, the pharmaceutical composition is in unit dosage form. Insuch form, the composition is divided into unit doses containingappropriate quantities of the active tricyclic tetrahydroquinoline. Theunit dosage form can be a packaged preparation, the package containingdiscrete quantities of the preparation, for example, packeted tablets,capsules, and powders in vials or ampules. The unit dosage form can alsobe a capsule, cachet, or tablet itself, or it can be the appropriatenumber of any of these packaged forms.

The following Examples are intended to illustrate but not limit thepresent invention.

EXAMPLE 1 Combinatorial Library Of Tricyclic TetrahydroquinolineDerivatives

This Example provides a representative solid-phase combinatorialsynthesis of a library which contains approximately 2774 derivatives oftricyclic tetrahydroquinoline (THQs).

Following the above Reaction Scheme II, preparation of a librarycontaining the THQs involves the following steps. Briefly, first, 19diverse aminobenzoic acids, varying at position of Y--R¹, R², R³ or R⁴without use of amino-protecting groups, were coupled to MBHA resinemploying the tea-bag method of Houghten et. al, as described, forexample in U.S. Pat. No. 4,631,211 to Houghten and Houghten et al.,Proc. Natl. Acad. Sci., 82:5131-5135 (1985), both of which areincorporated herein by reference. After coupling and thorough washingthe 19 tea-bags, each containing one resin-bound aminobenzoic acid, wereopened and the resin beads combined and thoroughly mixed in a largetea-bag as a suspension in dichloromethane (DCM). The resin mixture wasdried under vacuum, then divided into equal portions and resealed in 73labeled tea-bags, each tea-bag now containing a mixture of the 19aminobenzoic acids. This was followed by reaction with 73 aldehydes,each differing by their R⁵ substituent, and cyclopentadiene in thepresence of trifluoroacetic acid. After washing with a series ofsolvents, the resins were dried under vacuum and the mixturesindividually cleaved from the MBHA resin using a hydrogen fluoride (HF)procedure. The individual mixtures varying at Y--R¹, R², R³ or R⁴ andconstant at R⁵, each a mixture containing 38 individual compounds,including enantiomers, can then be tested for biological activity usingany one of a variety of screening assays, such as those described aboveor others well known in the art.

The individual aminobenzoic acids which were used to prepare the libraryof 2770 THQs include the following: anthranilic acid,2-amino-4-chlorobenzoic acid, 2-amino-4-fluorobenzoic acid,4-nitroanthranilic acid, 2-amino-5-bromobenzoic acid,2-amino-5-chlorobenzoic acid, 2-amino-5-fluorobenzoic acid,2-amino-5-iodobenzoic acid, 2-amino-5-methylbenzoic acid,2-amino-6-methylbenzoic acid, 4,5-difluoroanthranilic acid,3-amino-2-naphthoic acid, 4-aminobenzoic acid, 4-amino-2-chlorobenzoicacid, 4-amino-2-hydroxybenzoic acid, 4-amino-3-hydroxybenzoic acid,4-amino-3-methoxybenzoic acid, 4-amino-3-methylbenzoic acid,4-aminohuppuric acid.

Individual aldehydes which can be employed are as follows:paraformldehyde, benzaldehyde, chloroacetaldehyde,cyclohexanecarboxaldehyde, d,1-glyceraldehyde, glyoxylic acidmonohydrate, pyruvic aldehyde, salicylaldehyde, tribromoacetaldehyde,trimethylacetaldehyde, 1-methyl-2-pyrrolecarboxaldehyde,1-napthaldehyde, 2,3,4-trifluorobenzaldehyde,2,3,5-trichlorobenzaldehyde, 2,3-difluorobenzaldehyde,2,4-dichlorobenzaldehyde, 2,5-difluorobenzaldehyde,2,5-dimethylbenzaldehyde, 2,6-difluorobenzaldehyde, 2-bromobenzaldehyde,2-chloro-5-nitrobenzaldehyde, 2-chloro-6-fluorobenzaldehyde,2-cyanobenzaldehyde, 2-ethylbutyraldehyde, 2-fluorobenzaldehyde,2-formylphenoxyacetic acid, 2-methoxy-1-naphthaldehyde,2-nitro-5-chlorobenzaldehyde, 2-nitrobenzaldehyde,2-pyridinecarboxaldehyde, 3,4-(methylenedioxy)-6-nitrobenzaldehyde,3,4-difluorobenzaldehyde, 3,5-(trifluoromethyl)-bisbenzaldehyde,3,5-dichlorobenzaldehyde, 3-benzaldehyde, 3-bromo-4-fluorobenzaldehyde,3-bromobenzaldehyde, 3-carboxybenzaldehyde, 3-cyanobenzaldehyde,3-fluorobenzaldehyde, 3-formylchromone, 3-furaldehyde,3-hydroxybenzaldehyde, 3-nitro-4-chlorobenzaldehyde,3-nitrobenzaldehyde, 3-phenoxybenzaldehyde, 3-phenylbutyraldehyde,3-pyridinecarboxaldehyde, 4-bromo-2-thiophenecarboxaldehyde,4-bromobenzaldehyde, 4-carboxybenzaldehyde, 4-cyanobenzaldehyde,4-fluorobenzaldehyde, 4-nitrobenzaldehyde, 4-pyridinecarboxaldehyde,4-quinolinecarboxaldehyde, 5-bromosalicylaldehyde,5-nitro-2-furaldehyde, 5-norbomene-2-carboxaldehyde,6-methyl-2-pyridinecarboxaldehyde, 9-ethyl-3-carbazolecarboxaldehyde,2,3-dimethylvaleraldehyde, 2,2-dimethyl-4-pentenal,3-methoxy-2-nitro-benzaldehyde, 3-hydroxy-4-nitro-benzaldehyde,2-methylbutyraldehyde, 2-methylvaleraldehyde,4-chloro-3-nitro-benzaldehyde, trifluoro-p-tolualdehyde,2-methylundecanal.

1. Coupling of Aminobenzoic Acids to MBHA Resin

Nineteen polypropylene mesh packets (tea-bags, ˜3" square, 65 μ;McMaster Carr, Chicago, Ill.) of (5 g, 0.89 meq/g) MBHA resin wereprepared, washed with DCM (2×, ˜5 ml each), neutralized with 5%diisopropylethylamine/ dichloromethane (DIEA/DCM) (3×, ˜5 ml each), andwashed with DCM (2×, ˜5 ml each). Each resin packet was individuallycoupled overnight (˜16 hrs) by adding 5× aminobenzoic acid (0.5 M)in 1:1 DMF/DCM solvent system followed by 5× diisopropylcarbodiimide (DIC) inDCM (0.5 M) and hydroxybenzotriazole (HOBt) (5×). Following couplingcompletion, resin packets were washed with DCM (2×), DMF (2×), and DCM(1×) and MeOH (1×). After drying under vacuum 4-12 hrs, each individualpacket was then opened and the resin transfered to a large tea-bag(˜1.5" square) which was sealed and shaken in DCM for 1 hour. After aMeOH wash the mixed resin was dried under vacuum and then 75 mg portions(calc. 73 mmole) distributed into labeled tea-bags (˜1.5" square) foruse in subsequent chemistry.

2. Reaction of the Mixture of Resin-Bound Aminobenzoic Acids withAldehydes and Cyclopentadiene

Three tea-bags (2×75 mg aminobenzoic acid mixtures, and 35 mg4-aminobenzoic acid resin) were added to each solution of 73 aldehydes(1 M) in DMF (15 mL) and cooled in freezer (-10° C.) for 15-30 minutes.After cooling, 2.5 mL of cyclopentadiene (2M final concentration) wasadded and the solution cooled in the freezer again for 15-30 minutes.Then 1.16 mL of trifluoroacetic (1M) was added and the cyclizationreaction shaken for 45-50 hours at room temperature. Followingcompletion of the tricylic tetrahydroquinoline formation, the resinpackets were washed with DCM (2×), DMF (2×), and DCM (1×), MeOH (1×) anddried under vacuum.

3. Cleavage from the Resin

The tricyclic tetrahydroquinoline controls (4-aminobenzoic acid siblingbags) and mixtures were cleaved off the resin by treatment with HF(liquid (l)) at -15° C. for 2 hrs in the presence of anisole scavengerfollowed by warming to room temperature while removing HF (gaseous (g))with a nitrogen stream.

                  TABLE 1    ______________________________________    Experimental Data for Aminobenzamide Controls         Amide         formed                     Obs.*         upon      Yield  Yield                               Calc.                                    MW    .sup.1 H NMR    No.  cleavage  (mg)   (%)  MW   (M + 1)                                          (d6-DMSO)    ______________________________________    1    anthranil-                    8.5   83   136.1                                    137.1 7.90(b, 1H), 7.62         amide                            (d, 1H), 7.20-7.42(b         (2-amino-                        and dd, 2H), 6.88(d,         benzamide)                       1H), 6.75(dd, 1H),                                          5.30(vb)    2    2-amino-4-                    9.8   77   170.6                                    171.1 7.80(b, 1H), 7.52         chlorobenz-                      (d, 1H), 7.15(b,         amide                            1H), 6.71(d, 1H),                                          6.47(dd, 1H), 3.50                                          (vb, 2H)    3    2-amino-4-                    6.2   54   154.1                                    155.1 7.70(b, 1H), 7.47(t,         fluorobenz-                      1H), 7.08(b, 1H),         amide                            6.42(dd, 1H), 6.26                                          (ddd, 1H), 4.65(vb,                                          2H)    4    4-nitro-  10.7   79   181.1                                    182.1 8.02(b, 1H), 7.69         anthranil-                       (d, 1H), 7.54(d,         amide                            1H), 7.43(b, 1H),                                          7.22(dd, 1H), 4.45                                          (vb)    5    2-amino-5-                   11.2   69   215  215.1 7.83(b, 1H), 7.66         bromobenz-                 216.9 (d, 1H), 7.29-7.13         amide                            (dd and b, 2H),                                          6.80-6.52(b                                          and d, 3H)    6    2-amino-5-                    9.1   71   170.6                                    171.1 7.83(b, 1H), 6.71         chlorobenz-                      (d, 1H)7.30-7.09(b         amide                            and dd, 2H), 7.77-                                          7.60(b and d, 3H)    7    2-amino-5-                    8.8   76   154.1                                    155   7.80(b, 1H), 7.43         fluorobenz-                      (dd, 1H), 7.25(b,         amide                            1H), 7.06(ddd, 1H),                                          6.73(dd, 1H), 4.97                                          (vb)    8    2-amino-5-                   14.1   72   262  262.9 7.93-7.78(b and d,         iodobenz-                        2H), 7.38(dd, 1H),         amide                            7.25(b;1H), 6.54                                          (d, 1H), 3.45(vb,                                          2H)    9    2-amino-5-                   11.1   99   150.2                                    151.1 7.82(b, 1H), 7.41(s,         methylbenz-                      1H), 7.19(b, 1H),         amide                            7.05(dd, 1H), 6.70                                          (dd, 1H), 3.55(vb),                                          2.17(s, 3H)    10   2-amino-6-                    9.2   82   150.2                                    151.2 7.80(b, 1H), 7.63         methylbenz-                      (b, 1H), 7.16(dd,         amide                            1H), 6.69(dd, 2H),                                          3.67(vb), 2.27(s,                                          3H)    11   4,5-difluoro-                    4.4   34   172.1                                    173.1 7.78(b, 1H), 7.63         anthranil-                       (dd, 1H), 7.22(b,         amide                            1H), 6.62(dd, 1H),                                          3.70(vb)    12   3-amino-2-                    9.4   67   186.2                                    187.1 8.17(b and s, 2H),         naphthamide                      7.95(2, 1H), 7.76                                          (d, 1H), 7.60(d,                                          1H), 7.58(b, 1H)                                          738(dd, 1H), 7.10                                          (dd, 1H), 7.08(s,                                          1H)    13   4-amino-   9.5   93   136.1                                    137.3 7.64(d, 2H), 6.65         benzamide                        (d, 1H), 5.10(vb)    14   4-amino-2-                    8.8   69   170.6                                    171.6 7.57(b, 1H), 7.22(d,         chlorobenz-                      2H), 6.63(d, 1H),         amide                            6.53(d, 1H), 4.10                                          (vb)    15   4-amino-2-                   10.4   91   152.1                                    153.3 7.60(b, 1H), 7.28(s,         hydroxy-                         1H), 7.21(d, 1H),         benzamide                        6.94(b, 1H), 6.71                                          (d, 1H), 3.50(vb)    16   4-amino-3-                   10     88   152.1                                    153.4 7.90(b, 1H), 7.50(d,         hydroxy-                         1H), 6.11(d, 1H),         benzamide                        6.05(s, 1H), 5.35                                          (vb)    17   4-amino-3-                   11     88   166.2                                    167.2 7.71(b, 1H), 7.41(s,         methoxy-                         1H), 7.36(d, 1H),         benzamide                        7.11(b, 1H), 6.80                                          (d, 1H), 4.70(vb),                                          3.72(s, 3H)    18   4-amino-3-                    9.2   82   150.2                                    151.3 7.75-7.48(b and s         methylbenz-                      and d, 3H), 6.94(b,         amide                            1H), 6.75(d, 1H),                                          4.60(vb), 2.13(s,                                          3H)    19   4-amino-  14.1   97   193.2                                    194.1 8.76(b, 0.5H), 8.57         hippuric                         (b, 0.5H), 8.44(b,         amide (N-                        0.5H), 8.23(b,         (4-amino)-                       0.5H), 7.83(dd, 2H),         benzoyl-                         7.62(m, 4H), 7.33         amino-acet-                      (bd, 1H), 7.00(bd,         amide)                           1H), 6.62(d, 2H)    ______________________________________     *Obs. MW (M + 1) = Observed MW (M + 1)

                                      TABLE 2    __________________________________________________________________________    Experimental Data for Tricylic Tetrahydroquinoline Control Compounds     2-Substituted-3,4-(1'-propenyl)-6-carboxamide quinoline!                      HPLC                      RT  25                      cm (l) or       2-Substituent                Yield                   %  5 cm (s)                           Calc.                              MW Found    No.       (R.sup.1)                (mg)                   Yield                      column!                           MW (MALDI)                                     NMR(d, DMSO)    __________________________________________________________________________    1  hydrogen 7.7                   120                      49.49 (1)                           214.2                              (ND)   7.70-7.35(m+ s, 4H), 6.94(m, 1H),                                     5.68(dd, 1H),                              Not    5.62(dd, 1H), 3.84(dd, 1H), 2.95-2.40                              Determined                                     (mm+DMSO, calc 4H), 2.22(dd, 1H)    2  phenyl   7.8                   90 2.16 (s)                           290.4                              291.4  7.70-6.50(mm, 10H), 6.15(b, 1H),                                     5.85(dd, 1H),                              (M + 1)                                     5.55(dd, 1H), 4.60(dd, 1H), 4.04(dd,                                     1H), 3.85-                                     3.25(mm+H2O, calc 2H), 2.90(dd, m),                                     1.60(m,                                     1H)    3  chloroacetyl                7.1                   90 19.80 (s)                           262.7                              245.3  7.73(s, 1H), 7.36(dd, 1H), 7.25-6.60(mm,                                     3H),                              (--NH3)                                     6.62(d, 1H), 5.92(dd, 1H), 5.64(dd, 1H),                                     3.93(dd,                                     1H), 3.80-3.25(mm+H2O, calc 4H),                                     2.88(dd, 1H),                                     2.22(m, 1H)    4  cyclohexane-                7.2                   81 55.79 (1)                           296.4                              297.4  7.65-7.30(b+s+d, 3H), 6.81(b, 1H),                                     6.67(d, 1H),       carboxyl               (M + 1)                                     5.85(dd, 1H), 5.62(dd, 1H), 5.38(b, 1H),                                     3.85(dd,                                     0.5H), 3.72(m, 0.5H), 3.00(dd, 0.5H),                                     2.82(m,                                     0.5H), 2.28-0.85(mm, 14H)    5  D,L-glyceryl                6  73 27.55 (1)                           274.3                              257.4  7.78-7.30(b+d, 2H), 7.25-6.60(b+m, 2H),                                     6.60(d,                              (--NH3)                                     1H), 6.15(dd, 1H), 6.03(dd, 1H),                                     4.41(dd, 1H),                                     3.70(m, 2H), 3.07(d, 1H), 2.88(m, 1H),                                     2.62 dd,                                     1H), 2.32-01.90(mm, 3H)    6  carboxy  8.6                   111                      2.37 (s)                           258.3                              (ND)   7.70-6.70(mm, 6H), 5.85(dd, 1H),                                     5.63(dd, 1H),                                     4.05(dd, 1H), 3.64(d, 1H), 3.17(ddd,                                     1H), 2.28(m,                                     1H)    7  β-  7.3                   62 5.14 (s)                           392.5                              (ND)   7.70-6.55(mm, 15H), 6.08(b, 1H), 5.90(m,                                     1H),       phenylcinnamyl                5.75(m, 1H), 5.42(d, 1H), 4.02(dd, 1H),                                     3.00(m,                                     1H), 2.62(m, 1H), 2.14(m, 1H)    8  acetyl   6.7                   87 4.35 (s)                           256.3                              (ND)   7.85(s, 1H), 7.70-6.85(m, 5H), 5.82(m,                                     1H), 5.74                                     (m, 1H), 3.90(m, 1H), 3.00-2.50(mm,calc.                                     6H),                                     2.22(m, 1H)    9  2-hydroxyphenyl                9.2                   100                      37.93 (1)                           306.4                              307.5  7.70-6.55(mm, 10H), 5.92(dd, 1H),                                     5.58(dd, 1H),                              (M + 1)                                     4.82(d, 1H), 4.04(dd, 1H), 3.70(m, 2H),                                     3.15(ddd,                                     1H), 1.62(m, 1H)    10 tribromoacetyl                8.2                   59 4.00 (s)                           465                              387.2 (--Br)                                     7.70-6.55(mm, 5H), 6.17(d, 1H), 5.98(dd,                                     1H),                                     5.70(dd, 1H), 3.98(dd, 1H), 3.90(dd,                                     1H), 3.60(m,                                     2H), 3.12(ddd, 1H), 2.25(m, 1H)    11 trimethylacetyl                6.2                   76 4.31 (s)                           270.4                              271.4  7.65-7.30(mm, 3H), 6.95-6.70(mm, 2H),                                     5.92(dd,                              (M + 1)                                     1H), 5.68(dd, 1H), 5.45(b, 1H), 3.90(dd,                                     1H), 3.80-                                     3.10(mm+H20, calc2H), 82(ddd, 1H),                                     2.23(m,                                     1H), 1.25-0.88(m+s, 10H)    12 1-napthyl                6.1                   60 4.60 (s)                           340.4                              (ND)   8.32(m, 1H), 8.10-7.45(mm, 9H), 7.15(b,                                     1H), 6.94                                     (b, 1H), 6.18(b, 1H), 5.94(m, 1H),                                     5.58(m, 1H),                                     5.42(d, 1H), 4.24(dd, 1H), 3.28(m, 1H),                                     1.55(m,                                     1H)    13 2,3,4-   9.5                   92 4.49 (s)                           344.3                              345.3  7.65(s, 1H), 7.50-7.25(mm, 4H), 6.95(b,                                     1H), 6.82       trifluorophenyl        (M + 1)                                     (b, 1H), 6.72(d, 1H), 6.26(b, 1H),                                     5.90(dd, 1H),                                     5.58(dd, 1H), 4.84(d, 1H), 4.08(dd, 1H),                                     2.98(ddd,                                     1H), 2.34(m, 1H), 1.72(m, 1H)    14 2,3,5-   5.6                   47 5.10 (s)                           393.7                              395.3  7.85(s, 1H), 7.70-7.53(mm, 3H), 7.45(d,                                     1H), 6.97       trichlorophenyl        (M + 2)                                     (b, 1H), 6.80(b, 1H), 6.71(d, 1H),                                     6.19(b, 1H), 5.93                                     (dd, 1H), 5.59(dd, 1H), 4.88(d, 1H),                                     4.08(dd, 1H),                                     2.98(m, 1H), 2.34(m, 1H), 1.64(m, 1H)    15 2,3-     6.7                   68 48.19 (1)                           326.4                              327.3  7.70-6.65(mm, 8H), 6.15(b, 1H), 5.90(dd,                                     1H),       difluorophenyl         (M + 1)                                     5.58(dd, 1H), 4.88(s, 1H), 4.08(dd, 1H),                                     3.04(m,                                     1H), 1.70(m, 1H)    16 2,4-dichlorophenyl                9  84 4.84 (s)                           359.3                              (ND)   7.70-7.35(mm, 4H), 6.90(b, 1H), 6.80(d,                                     1H), 6.12                                     (b, 1H), 5.92(dd, 1H), 5.58(dd, 1H),                                     4.84(s, 1H),                                     4.08(dd, 1H), 3.05(m, 1H), 1.62(m, 1H)    17 2,5-     8.4                   86 4.32 (s)                           342.8                              343.3  7.65(s, 1H), 7.53-7.10(mm, 5H), 6.95(b,                                     1H), 6.80       difluorophenyl                (b, 1H), 6.70(d, 1H), 6.14(b, 1H),                                     5.88(dd, 1H),                                     5.58(dd, 1H), 4.80(d, 1H), 4.05(dd, 1H),                                     2.98(ddd,                                     1H), 2.36(ddd, 1H), 1.68(ddd, 1H)    18 2,5-     7.9                   83 4.60 (s)                           318.4                              319.3  7.65(s, 1H), 7.40(d, 1H), 7.30(s, 1H),                                     7.10-6.75       dimethylphenyl         (M + 1)                                     (mm, 4H), 6.66(d, 1H), 5.95(b, 1H),                                     5.88(dd, 1H),                                     5.58(dd, 1H), 4.72(s, 1H), 4.04(dd, 1H),                                     2.96(m,                                     1H), 2.45-2.15(m+s, 7H), 1.60(ddd, 1H)    19 2,6-     8.6                   88 4.08 (s)                           326.4                              327.2  7.68(s, 1H), 7.40(d, 1H), 7.20-6.70(mm,                                     5H), 6.64       difluorophenyl         (M + 1)                                     (d, 1H), 6.34(b, 1H), 5.88(dd, 1H),                                     5.60(dd, 1H),                                     4.94(s, 1H), 4.06(dd, 1H), 2.94(m, 1H),                                     2.64(m,                                     1H), 1.98(m, 1H)    20 2-bromophenyl                9  81 4.59 (s)                           369.3                              (ND)   7.70-7.15(mm, 7H), 6.85(b, 1H), 6.70(d,                                     1H), 6.14                                     (b, 1H), 5.92(dd, 1H), 5.60(dd, 1H),                                     4.82(s, 1H),                                     4.05(dd, 1H), 3.10(m, 1H), 1.60(m, 1H)    21 2-chloro-5-                8.1                   73 4.40 (s)                           369.8                              370.2  8.40(s, 1H), 8.20(d, 1H), 7.80(d, 1H),                                     7.58(s, 1H),       nitrophenyl            (M + 1)                                     7.42(d, 1H), 6.98(b, 1H), 6.82(b, 1H),                                     6.72(d, 1H),                                     6.28(b, 1H), 5.94(dd, 1H), 5.58(dd, 1H),                                     4.92(s,                                     1H), 4.10(dd, 1H), 3.12(m, 1H), 2.35(m,                                     1H), 1.60                                     (ddd, 1H)    22 2-chloro-6-                9  88 4.28 (s)                           342.8                              343.3  7.70-6.45(mm, 8H), 5.94-5.84(b+dd, 2H),                                     5.64(dd,       fluorophenyl           (M + 1)                                     1H), 5.08(s, 1H), 4.05(dd, 1H), 3.05(m,                                     1H), 1.90                                     (m, 1H)    23 2-cyanophenyl                8.6                   91 2.59 (s)                           315.4                              (ND)   8.42(m, 1H), 8.20-6.70(mm, 8H), 6.28(b,                                     1H), 5.92                                     (m, 1H), 5.65(m, 1H), 3.95(s, 1H),                                     2.88(m, 1H),                                     2.25(m, 1H), 1.20(m, 1H)    24 2-ethylbutyryl                7.5                   88 4.63 (s)                           284.4                              285.3  7.70-6.65(mm, 5H), 5.88(dd, 1H),                                     5.64(dd, 1H),                              (M + 1)                                     5.34(s, 1H), 3.90(dd, 1H), 3.25(m, 1H),                                     2.80(m,                                     1H), 2.25(m, 1H), 1.80-0.70(mm, 10H)    25 2-fluorophenyl                7.7                   83 4.23 (s)                           308.4                              309.2  7.70-7.10(mm, 6H), 6.96(b, 1H), 6.80(b,                                     1H), 6.70                              (M + 1)                                     (d, 1H), 6.18(b, 1H), 5.88(dd, 1H),                                     5.56(dd, 1H),                                     4.82(s, 1H), 4.05(dd, 1H), 2.96(m, 1H),                                     2.35(m,                                     1H), 1.64(ddd, 1H)    26 2-nitro-5-                7  63 4.35 (s)                           369.8                              370.2  8.05(d, 1H), 7.85(m, 1H), 7.70-7.45(mm,                                     3H), 7.15       chlorophenyl           (M + 1)                                     (b, 1H), 6.94(b, 1H), 6.65(d, 1H),                                     6.55(d, 1H), 6.20                                     (b, 1H), 5.94(dd, 1H), 5.55(dd, 1H),                                     4.98(s, 1H),                                     4.05(dd, 1H), 3.05(m, 1H), 1.90(m, 1H)    27 2-nitrophenyl                6.9                   69 4.14 (s)                           335.4                              (ND)   8.05-7.45(mm, 6H), 7.00(b, 1H), 6.84(b,                                     1H), 6.70                                     (d, 1H), 6.60(d, 1H), 6.20(b, 1H),                                     6.00(dd, 1H),                                     5.65(dd, 1H), 4.94(s, 1H), 4.05(dd, 1H),                                     3.10(m,                                     1H), 1.75(m, 1H)    28 3,4-     9.2                   81 4.13 (s)                           379.4                              380.3  7.73-7.25(mm, 4H), 6.95(b, 1H), 6.82(b,                                     1H), 6.72       (methylenedioxy)-      (M + 1)                                     (d, 1H), 6.35(b, 1H), 6.28(d, 2H),                                     5.95(dd, 1H),       6-nitrophenyl                 5.62(dd, 1H), 4.94(d, 1H), 4.04(dd, 1H),                                     3.08(m,                                     1H), 2.58(m, 1H), 1.65(ddd, 1H)    29 3,4-     10 102                      49.10 (1)                           326.4                              327.2  7.75-7.15(mm, 6H), 7.05(b, 1H), 6.82(b,                                     1H), 6.72       difluorophenyl         (M + 1)                                     (d, 1H), 6.20(s, 1H), 5.96(dd, 1H),                                     5.70(dd, 1H),                                     4.64(s, 1H), 4.07(dd, 1H), 2.94(m, 1H),                                     1.68(ddd,                                     1H)    30 3,5-bis- 10.6                   83 4.95 (s)                           426.4                              427.3  8.12(s, 2H), 8.05(s, 1H), 8,00(d, 1H),                                     7.60(s, 1H),       (trifluoromethyl)-     (M + 1)                                     7.45(d, 1H), 7.00(b, 1H), 6.80(b, 1H),                                     6.70(d, 1H),       phenyl                        6.35(s, 1H), 5.92(dd, 1H), 5.06(dd, 1H),                                     4.85(d,                                     1H), 4.05(dd, 1H), 3.05(ddd, 1H),                                     2.30(m, 1H),                                     1.55(m, 1H)    31 3,5-dichlorophenyl                8.2                   76 4.82 (s)                           359.3                              359.2  7.70-7.30(mm, 6H), 7.00(b, 1H), 6.78(b,                                     1H), 6.74                                     (d, 1H), 6.20(s, 1H), 5.94(dd, 1H),                                     5.62(dd, 1H),                                     4.65(s, 1H), 4.05(dd, 1H), 2.98(m, 1H),                                     1.70(ddd,                                     1H)    32 3-(3,4-dichloro-                4.8                   35 5.55 (s)                           451.4                              451.1  7.70-6.65(mm, 10H), 6.68(d, 1H), 6.15(b,                                     1H),       phenoxy)phenyl                5.90(dd, 1H), 5.56(dd, 1H), 4.60(s, 1H),                                     4.02(dd,                                     1H), 2.96(m, 1H), 2.34(m, 1H), 1.68(m,                                     1H)    33 3-(4-methoxy-                10.6                   86 4.86 (s)                           412.5                              (ND)   7.70-6.55(mm, 13H), 6.16(b, 1H), 5.95(m,                                     1H),       phenoxy)phenyl                5.62(m, 1H), 4.58(d, 1H), 4.04(dd, 1H),                                     3.68(s,                                     3H), 2.94(m, 1H), 2.32(m, 1H), 1.62(m,                                     1H)    34 3-(4-methyl-                7.8                   66 5.08 (s)                           396.2                              (ND)   7.65-6.50(mm, 13H), 6.18(b, 1H), 5.94(m,                                     1H),       phenoxy)phenyl                5.62(m, 1H), 4.62(d, 1H), 4.04(dd, 1H),                                     3.68(s,                                     3H), 2.94(m, 1H), 2.32(m, 1H), 1.62(m,                                     1H)    35 3-bromo-4-                13.4                   115                      4.61 (s)                           387.3                              387.2  7.80-7.25(mm, 4H), 6.92(b, 1H), 6.80(b,                                     1H), 6.70       fluorophenyl           389.1  (d, 1H), 6.22(b, 1H), 5.90(dd, 1H),                                     5.58(dd, 1H),                                     4.62(d, 1H), 4.02(dd, 1H), 2.94(ddd,                                     1H), 2.32                                     (ddd, 1H), 1.65(ddd, 1H)    36 3-bromophenyl                9.3                   84 4.51 (s)                           369.3                              (ND)   7.95-7.15(mm, 7H), 7.05(b, 1H), 6.82(b,                                     1H), 6.70                                     (d, 1H), 6.24(s, 1H), 5.95(dd, 1H),                                     5.60(dd, 1H),                                     4.64(d, 1H), 4.08(dd, 1H), 2.94(m, 1H),                                     1.68(m,                                     1H)    37 3-carboxyphenyl                9.9                   99 3.56 (s)                           334.4                              335.2  8.05(s, 1H), 7.80(d, 1H), 7.75-7.42(mm,                                     4H), 6.90                              (M + 1)                                     (b, 1H), 6.85(b, 1H), 6.68(d, 1H),                                     6.20(b, 1H), 5.92                                     (dd, 1H), 5.55(dd, 1H), 4.66(s, 1H),                                     4.05(dd, 1H),                                     2.94(m, 1H), 2.35(m, 1H), 1.60(ddd, 1H)    38 3-cyanophenyl                10.8                   114                      3.95 (s)                           315.4                              (ND)   8.00-7.25(mm, 7H), 7.00(b, 1H), 6.80(b,                                     1H), 6.72                                     (d, 1H), 6.24(s, 1H), 5.95(dd, 1H),                                     5.60(dd, 1H),                                     4.70(d, 1H), 4.10(dd, 1H), 3.00(m, 1H),                                     1.65(m,                                     1H)    39 3-fluorophenyl                9.1                   98 4.24 (s)                           308.4                              309.3  7.65-6.64(mm, 9H), 6.15(b, 1H), 5.90(dd,                                     1H),                              (M + 1)                                     5.55(dd, 1H), 4.62(d, 1H), 4.04(dd, 1H),                                     2.94(m,                                     1H), 2.35(m, 1H), 1.62(m, 1H)    40 3-chromone                8.7                   81 3.86 (s)                           358.3                              (ND)   8.38(s, 1H), 8.12(d, 1H), 7.90-7.40(mm,                                     7H), 7.05                                     (b, 1H), 6.86(b, 1H), 6.70(d, 1H),                                     5.95(m, 2H),                                     5.62(dd, 1H), 4.72(s, 1H), 4.08(dd, 1H),                                     3.15(m,                                     1H), 1.95(m, 1H)    41 3-hydroxyphenyl                9.4                   102                      3.52 (s)                           306.4                              (ND)   7.65-6.45(mm, 10H), 6.10(b, 1H),                                     5.92(dd, 1H),                                     5.58(dd, 1H), 4.50(d, 1H), 4.02(dd, 1H),                                     2.88(m,                                     1H), 1.68(m, 1H)    42 3-       10 104                      4.16 (s)                           320.4                              (ND)   7.62-6.50(mm, 9H), 6.12(b, 1H), 5.90(dd,                                     1H),       methoxyphenyl                 5.58(dd, 1H), 4.62(m, 1H), 4.05(m, 1H),                                     2.92(m,                                     1H), 2.40-2.15(m+s, 4H), 1.72(m, 1H)    43 3-methylphenyl                6.5                   71 4.43(s)                           304.4                              (ND)   7.60-6.45(mm, 9H), 6.12(b, 1H), 5.88(dd,                                     1H),                                     5.56(dd, 1H), 4.55(d, 1H), 4.02(dd, 1H),                                     2.90(m,                                     1H), 2.40-1.90(mm, 5H), 1.60(m, 1H)    44 3-nitro-4-                9.4                   85 4.33 (s)                           369.8                              370.2  8.08 (s, 1H), 7.78(s, 2H), 7.65(s, 1H),                                     7.44(s, 1H),       chlorophenyl           (M + 1)                                     6.95(b, 1H), 6.80(b, 1H), 6.30(b, 1H),                                     5.92(dd,                                     1H), 5.58(dd, 1H), 4.72(d, 1H), 4.04(dd,                                     1H), 3.00                                     (m, 1H), 2.30(ddd, 1H), 1.65(ddd, 1H)    45 3-nitrophenyl                8.4                   83 4.13 (s)                           335.4                              (ND)   8.50(d, 1H), 8.15(dd, 1H), 7.90(d, 1H),                                     7.72-7.52                                     (mm, 3H), 7.42(d, 1H), 7.00(b, 1H),                                     6.83(b, 1H),                                     6.70(d, 1H), 6.32(s, 1H), 5.92(dd, 1H),                                     5.55(dd,                                     1H), 4.68(d, 1H), 4.05(dd, 1H),                                     3.05(ddd, 1H),                                     2.32(ddd, 1H), 1.60(m, 1H)    46 3-       9.2                   80 4.88 (s)                           382.5                              382.4  7.70-6.60(mm, 10H), 6.14(b, 1H),                                     5.92(dd, 1H),       phenoxyphenyl                 5.5.8(dd, 1H), 4.60(d, 1H), 4.04(dd,                                     1H), 2.90(m,                                     1H), 2.30(m, 1H), 1.65(m, 1H)    47 2-phenylpropyl                10.3                   103                      3.59 (s)                           332.5                              (ND)   8.28(s, 1H), 8.16(d, 1H), 8.02(d, 1H),                                     7.65-6.75                                     (mm, 6H), 7.42(d, 1H), 6.64(d, 0.5H),                                     6.45(d,                                     0.5H), 5.84(dd, 1H), 5.62(m, 1H),                                     4.55(m, 0.5H),                                     4.32(m, 1H), 3.75-3.00(mm+H2O, calc.                                     5H), 2.24                                     (m, 2H), 1.80-1.10(mm, 7H)    48 3-pyridine-carboxyl                7.5                   86 (ND) 291.4                              (ND)   8.72(s, 1H), 8.55(d, 1H), 8,00(d, 1H),                                     7.65-7.35                                     (mm, 3H), 7.00(b, 1H), 6.76(b, 1H),                                     6.70(d, 1H),                                     6.28(s, 1H), 5.94(dd, 1H), 5.06(dd, 1H),                                     4.72(d,                                     1H), 4.05(dd, 1H), 3.00(m, 1H), 2.30(m,                                     1H), 1.64                                     (m, 1H)    49 4-bromo-2-                5.8                   52 4.47 (s)                           375.3                              375.2  8.10-6.50(mm, 8H), 5.90(dd, 1H),                                     5.62(dd, 1H),       thiophene-carboxyl     377.2  4.85(d, 1H), 4.02(dd, 1H), 3.15(m, 1H),                                     2.85(m,                                     1H), 1.90(m,1H)    50 4-bromophenyl                8.7                   79 4.62 (s)                           369.3                              369.4  7.85-6.45(mm, 10H), 6.15(b, 1H),                                     5.92(dd, 1H),                              371.1  5.58(dd, 1H), 4.68(d, 1H), 4.02(dd, 1H),                                     2.88(m,                                     1H), 2.45(m, 1H), 1.68(m, 1H)    51 4-carboxyphenyl                10.3                   103                      35.05 (1)                           334.4                              335.3  7.92(s, 2H), 8.05(s, 1H), 8.00(d, 1H),                                     7.60(s, 1H),                              (M + 1)                                     7.45(d, 1H), 7.02(b, 1H), 6.82(b, 1H),                                     6.70(d, 1H),                                     6.25(b, 1H), 5.92(dd, 1H), 5.58(dd, 1H),                                     4.68(s,                                     1H), 4.05(dd, 1H), 2.95(ddd, 1H),                                     2.34(m, 1H),                                     1.60(m, 1H)    52 4-cyanophenyl                8.3                   88 3.98 (s)                           315.4                              (ND)   7.85(d, 2H), 7.70-7.50(mm, 3H), 7.45(d,                                     1H), 7.08                                     (b, 1H), 6.82(b, 1H), 6.68(d, 1H),                                     6.25(b, 1H), 5.90                                     (dd, 1H), 5.55(dd, 1H), 4.70(s, 1H),                                     4.05(dd, 1H),                                     2.95(m, 1H), 2.30(m, 1H), 1.55(m, 1H)    53 4-fluorophenyl                9.5                   103                      4.20 (s)                           308.4                              309.4  7.80-6.68 (mm, 9H), 6.20(b, 1H),                                     5.94(dd, 1H),                              (M + 1)                                     5.58(dd, 1H), 4.62(s, 1H), 4.04(dd, 1H),                                     2.90(ddd,                                     1H), 2.35(m, 1H), 1.62(m, 1H)    54 4-methoxy-1-                9.2                   83 4.60 (s)                           370.5                              (ND)   8.20(m, 1H), 7.88-6.45(mm, 11H), 5.90(m,                                     1H),       naphthyl                      5.68(m, 1H), 3.95(s, 3H), 3.18(m, 1H),                                     2.10(m,                                     1H), 1.62(m, 1H)    55 4-nitrophenyl                7.7                   77 4.16 (s)                           335.4                              336.2  8.24(d, 2H), 7.70(d, 2H), 7.58(s, 1H),                                     7.45(d, 1H),                              (M + 1)                                     6.95(b, 1H), 6.80(b, 1H), 6.70(d, 1H),                                     6.30(b, 1H),                                     5.92(dd, 1H), 5.55(dd, 1H), 4.75(s, 1H),                                     4.06(dd,                                     1H), 2.98(ddd, 1H), 2.32(ddd, 1H),                                     1.56(ddd, 1H)    56 4-pyridine-carboxyl                8.2                   94 1.81 (s)                           291.4                              292.4  8.85(b, 2H), 7.70(b, 2H), 7.50(s, 1H),                                     7.45(d, 1H),                              (M + 1)                                     6.98(b, 1H), 6.82(b, 1H), 6.74(dd, 1H),                                     6.30(b,                                     1H), 5.94(dd, 1H), 5.58(dd, 1H), 4.72(s,                                     1H), 4.03                                     (dd, 1H), 3.05(m, 1H), 2.30(m, 1H),                                     1.62(m, 1H)    57 4-quinoline-                10 98 2.42 (s)                           341.4                              342.2  8.45(d, 2H), 8.12(d, 2H), 7.92-7.58(m,                                     6H), 7.45       carboxyl               (M + 1)                                     (d, 1H), 6.95(b, 1H), 6.75(d, 1H),                                     6.24(b, 1H), 5.96                                     (dd, 1H), 5.52(dd+s, 2H), 4.24(dd, 1H),                                     3.15(m,                                     1H), 2.32(m, 1H), 1.42(ddd, 1H)    58 5-bromo-2-                10.3                   89 4.12 (s)                           385.3                              (ND)   7.90-6.50(mm, 9H), 5.88(dd, 1H),                                     5.58(dd, 1H),       hydroxyphenyl                 4.75(d, 1H), 4.00(dd, 1H), 3.10(ddd,                                     1H), 2.30(m,                                     1H), 1.60(m, 1H)    59 5-nitro-2-furyl                35.1                   360                      3.78 (s)                           325.3                              326.2  7.72(1, 2H), 7.60(s, 1H), 7.45(d, 1H),                                     7.15-6.58                              (M + 1)                                     (mm, 4H), 6.36(b, 1H), 5.88(dd, 1H),                                     5.60(dd, 1H),                                     4.72(d, 1H), 4.05(dd, 1H), 3.10(ddd,                                     1H), 2.40(m,                                     1H), 2.10(m, 1H)    60 5-norbornen-2-yl                7.2                   78 5.38 (s)                           306.4                              (ND)   7.50(s, 1H), 7.38(d, 1H), 7.20-6.65(mm,                                     6H), 5.88                                     (dd, 1H), 5.65(dd, 1H), 3.90(dd, 1H),                                     3.22(m, 1H),                                     3.10-2.10(mm+DMSO, calc. 5H),                                     1.80-1.25(mm,                                     4H)    61 1,2-     7.5                   84 4.88 (s)                           298.4                              299.4  7.58(b, 1H), 7.48(s, 1H), 7.35(d, 1H),                                     6.85(b, 1H),       dimethylbutyl          (M + 1)                                     6.72(d, 1H), 5.88(dd, 1H), 5.65(dd, 1H),                                     5.33(b,                                     1H), 3.90(dd, 1H), 3.12(m, 1H), 2.78(m,                                     1H), 2.22                                     (m, 2H), 1.85(m, 1H), 1.60-0.70(mm,                                     12H)    62 1,1-dimethyl-3-                7.7                   87 4.37 (s)                           296.4                              (ND)   8.15(s, 1H), 7.78(s, 1H), 7.60-30(m,                                     4H), 6.82(b,       butyl                         2H), 6.70(d, 1H), 6.52(d, 1H), 5.90(dd,                                     1H), 5.62                                     (dd, 1H), 3.85(dd, 1H), 2.80(m, 1H),                                     2.20(m, 1H),                                     1.75(m, 1H), 1.35-0.85(mm, 8H)    63 3-methoxy-2-                7.8                   71 4.18 (s)                           365.4                              366.2  7.68-7.15(mm, 5H), 6.95(b, 1H), 6.82(b,                                     1H), 6.75       nitrophenyl            (M + 1)                                     (d, 1H), 6.24(b, 1H), 5.88(dd, 1H),                                     5.58(dd, 1H),                                     4.38(d, 1H), 3.95(dd, 1H), 3.85(s, 3H),                                     2.78(ddd,                                     1H), 2.35(m, 1H), 1.68(ddd, 1H)    64 3-hydroxy-4-                7.9                   75 4.10 (s)                           351.4                              352.1 (M + 1)                                     7.90(d, 1H), 7.58(s, 1H), 7.42(d, 1H),                                     7.20(s, 1H), 7.04(d,       nitrophenyl                   1H), 6.92(b, 1H), 6.80(b, 1H), 6.68(d,                                     1H), 6.22(b, 1H), 5.94                                     (dd, 1H), 5.56(d, 1H), 4.60(s, 1H),                                     4.04(dd, 1H), 2.92(m,                                     1H), 2.32(m, 1H), 1.64(m, 1H)    65 2-methylbutyryl                7.1                   88 4.34 (s)                           270.4                              271.3  7.80(b, 1H), 7.45(s, 1H), 7.36(d, 1H),                                     6.75(b, 2H), 6.68(d,                                     1H), 5.85(dd, 1H), 5.61(dd, 1H),                                     3.86(dd, 1H), 3.03(dd, 1H),                                     2.78(m, 1H), 2.22(ddd, 1H),                                     1.75-0.75(mm, 10H)    66 1-methylbutyl                7.9                   93 4.60 (s)                           284.4                              285.3 (M + 1)                                     7.60(b, 1H), 7.45(s, 1H), 7.38(d, 1H),                                     6.75(b, 2H), 6.70(d,                                     1H), 5.88(dd, 1H), 5.63(dd, 1H),                                     3.88(dd, 1H), 3.05(dd, 1H),                                     2.80(m, 1H), 2.22(m, 1H), 1.70-0.80(mm,                                     1.2H)    67 4-chloro-3-nitro-                8.3                   75 4.37 (s)                           369.8                              370.2 (M + 1)                                     8.12(s, 1H), 7.80(s, 2H), 7.60(s, 1H),                                     7.40(d, 1H), 6.94(b,       phenyl                        1H), 6.80(b, 1H), 6.70(d, 1H), 6.26(b,                                     1H), 5.92(dd, 1H),                                     5.56(d, 1H), 4.70(d, 1H), 4.04(dd, 1H),                                     2.98(ddd, 1H), 2.30                                     (ddd, 1H), 1.65(ddd, 1H)    68 trifluoro-p-toluyl                10.9                   101                      4.61 (s)                           358.4                              359.0 (M + 1)                                     7.85-7.45(mm, 6H), 7.08(b, 1H), 6.84(b,                                     1H), 6.68(d, 1H),                                     6.25(b, 1H), 5.92(dd, 1H), 5.58(dd, 1H),                                     4.72(s, 1H), 4.08                                     (dd, 1H), 2.95(m, 1H), 2.34(m, 1H),                                     1.60(m, 1H)    69 1-methyldecanyl                5.5                   50 6.47 (s)                           368.6                              (ND)   7.60(b, 1H), 7.45(s, 1H), 7.35(d, 1H),                                     6.75(b, 2H), 6.70(d,                                     1H), 6.50(b, 1H), 5.85(dd, 1H), 5.64(b,                                     1H), 3.88(dd, 1H),                                     3.05(dd, 1H), 2.80(m, 1H), 2.20(m, 1H),                                     1.65-0.75(mm,                                     24H)    __________________________________________________________________________

EXAMPLE 2 Combinatorial Library Of Branched TricyclicTetrahydroquinoline Derivatives

This Example provides a representative solid-phase combinatorialsynthesis of a library which contains approximately 17,000 derivativesof branched tricylic tetrahydroquinolines (THQs).

Following the above Reaction Scheme III, preparation of a librarycontaining the THQs involved the following steps. Briefly, first, L or DN-BOC p-nitrophenylalanine was attached to MBHA resin using tea-bags.After removal of the BOC protecting group, the nitrogen was acylatedwith 170 acid diverse derivatives creating a variation of the R⁸substitent, which, again employed the tea-bags to carry out theoperations. The acylated products were seperated into four new subsets(42 or 43 acids per group) by appropriate resin mixing techniques andthe nitro group converted to an amino functionality by reduction. The 8subgroups (L or D branch, four acid sets) were distributed into tea-bagsand reacted with 25 aldehydes and cyclopentadiene in the presence oftrifluoroacetic acid to generate new tricylic tetrahydroquinolinederivatives. After standard HF cleavage, the individual mixtures varyingat R⁸ and constant at Y--R¹ and R⁵, each a mixture containing either 84or 86 individual compounds, including enantiomers, which can then betested for biological activity.

The individual acids which were be used to prepare with a library of17,000 TTHQs include the following: acetic acid, butyric acid,cyclobutanecarboxylic acid, cycloheptanecarboxylic acid,cyclohexanebutyric acid, cyclohexanecarboxylic acid,cyclohexanepropionic acid, cyclohexylacetic acid, cyclopentanecarboxylicacid, cyclopentylacetic acid, hydrocinnamic acid, isobutyric acid,isovaleric acid, octanoic acid, propionic acid, tert-butylacetic acid,trimethylacetic acid, 1-adamantaneacetic acid,4-methyl-1-cyclohexanecarboxylic acid, 4-methylcyclohexaneacetic acid,4-methylvaleric acid, 2-ethyl-2-hexenoic acid, 2-ethylbutyric acid,2-ethylhexanoic acid, 2-methylbutyric acid,2-methylcyclopropanecarboxylic acid, 2-norbomaneacetic acid,2-phenylbutyric acid, 2-propylpentanoic acid, 3,3,3-triphenylpropionicacid, 3,3-diphenylpropionic acid, 4-tert-butyl-cyclohexanecarboxylicacid, 3,5,5-trimethylhexanoic acid, 5-phenylvaleric acid,3-(2-methoxyphenyl)propionic acid, 3-(3,4,5-trimethoxyphenyl)propionicacid, 3-(3,4-dimethoxyphenyl)propionic acid, heptanoic acid,3-cyclopentylpropionic acid, formic acid, lauric acid, 3-methylvalericacid, 3-phenylbutyric acid, α-cyclohexylphenylacetic acid,α-methylcinnamic acid, crotonic acid, ethoxyacetic acid,4-chlorocinnamic acid, 4-ethoxyphenylacetic acid, m-tolylacetic acid,methoxyacetic acid, p-tolylacetic acid, phenoxyacetic acid, phenylaceticacid, tiglic acid, trans-3-hexenoic acid, trans-cinnamic acid,trans-styrylacetic acid, triphenylacetic acid, 4-fluorophenylaceticacid, vinylacetic acid, (2,5-dimethoxyphenyl)acetic acid,(2-naphthoxy)acetic acid, (3,4-dimethoxyphenyl)acetic acid, (α, α,α-trifluoro-m-tolyl)acetic acid, (methylthio)acetic acid,1-(4-chlorophenyl)-1-cyclopentanecarboxylic acid, 1-naphthylacetic acid,1-phenyl-1-cyclopropanecarboxylic acid, 4-isobutyl-a-methylphenylaceticacid, 4-methoxyphenylacetic acid, 2,4-hexadienoic acid,2-(trifluoromethyl)-cinnamic acid, 2-chloro-4-fluorophenylacetic acid,2-naphthylacetic acid, 3,4,5-trimethoxycinnamic acid,3,4-dichlorophenylacetic acid, 3,4-dimethylbenzoic acid,3,4,5-trimethoxyphenylacetic acid, 3-benzoylpropionic acid,3-bromophenylacetic acid, 3-fluorophenylacetic acid,3-methoxyphenylacetic acid, 3-thiopheneacetic acid, 4-biphenylaceticacid, 4-bromophenylacetic acid, α,α,α-trifluoro-m-toluic acid,α,α,α-trifluoro-o-toluic acid, benzoic acid, niflumic acid, o-anisicacid, o-toluic acid, piperonylic acid, 1-napthoic acid,2,3-dichlorobenzoic acid, 2,3-dimethoxybenzoic acid, 2,4-dichlorobenzoicacid, 2,4-difluorobenzoic acid, 2,4-dimethoxybenzoic acid,2,4-dimethylbenzoic acid, 2,5-dichlorobenzoic acid, 2,5-dimethylbenzoicacid, 2,6-dichlorobenzoic acid, 2,6-difluorobenzoic acid,2,6-dimethoxybenzoic acid, 2-bromobenzoic acid,2-chloro-4,5-difluorobenzoic acid, 2-chlorobenzoic acid, 2-ethoxybenzoicacid, 2-fluorobenzoic acid, 2-napthoic acid, 3,4,5-triethoxybenzoicacid, 3,4,5-trimethoxybenzoic acid, 3,4-dichlorobenzoic acid,3,4-difluorobenzoic acid, 3,4-dimethoxybenzoic acid,3,5-bis(trifluoromethyl)-benzoic acid, 5-bromo-2-chlorobenzoic acid,3,5-dimethyl-p-anisic acid, 3-bromobenzoic acid, 3-chlorobenzoic acid,3-cyanobenzoic acid, 3-dimethylaminobenzoic acid,3-fluoro-4-methylbenzoic acid, 3-fluorobenzoic acid,3-iodo4-methylbenzoic acid, 3-phenoxybenzoic acid, 4-chloro-o-anisicacid.

Individual aldehydes which were employed are as follows: glyoxylic acidmonohydrate, 1-napthaldehyde, 2,3,4-trifluorobenzaldehyde,2,3,5-trichlorobenzaldehyde, 2,3-difluorobenzaldehyde,2,4-dichlorobenzaldehyde, 2,5-difluorobenzaldehyde,2,5-dimethylbenzaldehyde, 2,6-difluorobenzaldehyde, 2-bromobenzaldehyde,2-chloro-5-nitrobenzaldehyde, 2-fluorobenzaldehyde,3,4-(methylenedioxy)-6-nitrobenzaldehyde, 3,4-difluorobenzaldehyde,3,5-bis(trifluoromethyl)benzaldehyde, 3,5-dichlorobenzaldehyde,3-cyanobenzaldehyde, 3-fluorobenzaldehyde, 3-formylchromone,3-nitro-4-chlorobenzaldehyde, 3-phenoxybenzaldehyde,4-cyanobenzaldehyde, 4-pyridinecarboxaldehyde,3-methoxy-2-nitro-benzaldehyde, 3-hydroxy-4-nitro-benzaldehyde.

1. Coupling of L or D p-nitrophenylalanine to MBHA Resin Polypropylenemesh packets (tea-bags, ˜5") of (5 g each, 0.89 meq/g) MBHA resin wereprepared, washed with DCM (2×, ˜25 ml each), neutralized with 5%diisopropylethylamine/dichloromethane (DIEA/DCM) (3×, ˜25 ml each), andwashed with DCM (2×, ˜25 ml each). Each resin packet set wasindividually coupled 2-4 hrs by adding 2.5× L or D N-BOC p-nitrobenzoicacid (0.5 M) in 1:1 DMF/DCM solvent system followed by 2.5×diisopropyl-carbodiimide (DIC) in DCM (0.5 M) and HOBt (2.5×). Followingcoupling completion, resin packets were washed with DCM (2×), DMF (2×),and DCM (1×) and MeOH (1×). The N-BOC protecting group was removed byshaking the bags with a solution of 55% TFA in DCM at room temperaturefor 30 mins. The liquid was decanted and the packets were washed withDCM (3×), 5% DIEA in DCM (3×) DCM (3×) After drying under vacuum 4-12hrs, each individual packet was opened and the resin transfered in 75 mg(calc. 63 mmole) or 30 mg (calc. 25 mmole) portions to a small labeledtea-bags (˜1.5" square) for use in subsequent chemistry.

Acylation of L or D p-nitrophenylalanine.

The resin packets (2×75 mg and a 30 mg) were individually coupled with170 different acids overnight (˜16 hrs) by adding 5X acid (0.5 M) in 1:1DMF/DCM solvent system followed by 5× diisopropylcarbodiimide (DIC) inDCM (0.5 M) and HOBt (5×). Following coupling completion, resin packetswere washed with DCM (2×), DMF (2×), and DCM (1×) and MeOH (1×). The 30mg bags from each of the 170 acid reactions were cleaved by standard HFprocedures and the products analyzed (See Table 3). One of the 75 mgbags from each acid reaction was opened and combined into one of fourlarge tea-bags (˜5" square) and each then mixed in DCM for 30 min. Afterdrying under vacuum, the resin-bound acid mixture sets were distributedin 30 mg portions into 1" tea-bags for use in subsequent chemistry.

                                      TABLE 3    __________________________________________________________________________    Experimental Data for N-Acetoylated 4-Nitrophenylalanine                       HPLC RT (25                       cm (1) or 5 cm                              Expected                                   Observed    No.       N-acetoyl substituent (R.sup.1)                       (s) column)                              MW   MW    __________________________________________________________________________    1  acetyl          21.77 (l)                              251.31                                   (ND)Not                                   Determined    2  α-cyclohexylphenylacetyl                       43.60 (l)                              409.33                                   (ND)    3  α-methylcinnamoyl                       37.03 (l)                              353.4                                   (ND)    4  α,α,α,-trifluoro-m-toluoyl                       37.12 (l)                              381.33                                   (ND)    5  α,α,α,-trifluoro-o-toluoyl                       34.18 (l)                              381.33                                   (ND)    6  α,α,α,-trifluoro-p-toluoyl                       37.92 (l)                              381.33                                   (ND)    7  benzoyl         30.99 (l)                              313.31                                   (ND)    8  butyroyl        27.14 (l)                              279.32                                   (ND)    9  crotonoyl       26.52 (l)                              277.3                                   (ND)    10 cyclobutanecarboxoyl                       29.65 (l)                              291.33                                   (ND)    11 cycloheptanecarboxoyl                       35.88 (l)                              333.41                                   (ND)    12 cyclohexanebutyroyl                       41.29 (l)                              361.51                                   (ND)    13 cyclohexanecarboxoyl   319.41                                   (ND)    14 cyclohexanepropionoyl                       38.72 (l)                              347.43                                   (ND)    15 cyclobexylacetoyl                       35.32 (l)                              333.41                                   (ND)    16 cyclopentanecarboxoyl                       30.82 (l)                              305.35                                   (ND)    17 cyclopentylacetoyl                       33.48 (l)                              319.38                                   (ND)    18 ethoxyacetoyl   2.04 (s)                              295.32                                   (ND)    19 4-chlorocinnamoyl                       3.90 (s)                              373.82                                   (ND)    20 4-cyanobenzoyl  3.22 (s)                              338.34                                   (ND)    21 hydrocinnamoyl  34.00 (l)                              341.41                                   (ND)    22 4-(dimethylamino)benzoyl                       3.11 (s)                              356.4                                   (ND)    23 4-ethoxybenzoyl 3.53 (s)                              357.39                                   (ND)    24 isobutyroyl     26.86 (l)                              279.32                                   (ND)    25 isonicotinoyl   21.51 (l)                              314.32                                   (ND)    26 4-ethoxyphenylacetoyl                       3.47 (s)                              371.41                                   (ND)    27 isovaleroyl     29.78 (l)                              293.34                                   (ND)    28 4-ethylbenzoyl  3.71 (s)                              341.39                                   341.9    29 m-anisoyl       32.11 (l)                              343.36                                   (ND)    30 m-toluoyl       33.73 (l)                              327.36                                   (ND)    31 m-tolylacetoyl  34.29 (l)                              341.39                                   (ND)    32 methoxyacetoyl         281.29                                   (ND)    33 nicotinoyl      22.09 (l)                              314.31                                   (ND)    34 niflumoyl       4.32 (s)                              473.43                                   (ND)    35 o-anisoyl       4.51 (s)                              343.36                                   343.9    36 o-toluoyl       32.03 (l)                              327.36                                   (ND)    37 octanoyl        4.17 (s)                              335.42                                   (ND)    38 p-anisoyl       32.16 (l)                              343.41                                   (ND)    39 p-toluoyl       33.65 (l)                              327.41                                   (ND)    40 p-tolylacetoyl  34.28 (l)                              341.39                                   (ND)    41 phenoxyacetoyl  3.62 (s)                              343.36                                   343.9    42 phenylacetoyl   3.44 (s)                              327.41                                   (ND)    43 picolinoyl      3.22 (s)                              314.32                                   315.0 (M + 1)    44 piperonoyl      31.23 (l)                              357.34                                   (ND)    45 propionoyl      2.62 (s)                              261.25                                   (ND)    46 pyrrole-2-carboxyl                       2.90 (s)                              302.31                                   (ND)    47 4-fluoro-α-methylphenylacetoyl                       4.74 (s)                              359.38                                   359.8    48 4-fluorobenzoyl 3.29 (s)                              331.32                                   (ND)    49 4-fluorophenylacetoyl                       2.80 (s)                              345.35                                   (ND)    50 tert-butylacetoyl                       32.57 (l)                              307.41                                   (ND)    51 tetrahydro-2-furoyl                       2.61/2.68 (s)                              307.33                                   307.9    52 tetrahydro-3-furoyl                       2.39/2.45 (s)                              307.33                                   307.9    53 tigloyl         3.17(s)                              291.33                                   (ND)    54 trans-3-(3-pyridyl)acroyl                              340.36                                   (ND)    55 trans-3-hexenoyl                       32.34 (l)                              305.35                                   (ND)    56 trans-cinnamoyl        339.41                                   (ND)    57 trans-styrylacetoyl                       34.80 (l)                              353.4                                   (ND)    58 trimethylacetoyl                       40.52 (l)                              293.31                                   294.0 (M + 1)    59 triphenylacetoyl                       4.89 (s)                              479.54                                   (ND)    60 4-isobutyl-α-methylphenylacetoyl                       3.33 (s)                              397.5                                   (ND)    61 vinylacetoyl    26.32 (l)                              277.3                                   (ND)    62 xanthene-9-carboxyl                       3.57 (s)                              417.44                                   (ND)    63 (2,5-dimethoxyphenyl)acetoyl                              387.41                                   (ND)    64 (2-naphthoxy)acetoyl                       3.84 (s)                              393.42                                   (ND)    65 (3,4-dimethoxyphenyl)acetoyl                       29.03 (l)                              387.41                                   (ND)    66 (4-pyridylthio)acetoyl                       19.81 (l)                              360.41                                   361.2 (M + 1)    67 (α-α-α-trifluoro-m-tolyl)acetoyl                              395.36                                   (ND)    68 (methylthio)acetoyl                       2.68 (s)                              297.35                                   (ND)    69 (phenylthio)acetoyl                       3.51 (s)                              359.42                                   (ND)    70 1-(4-chlorophenyl)-1-                       27.83/28.67 (l)                              415.9                                   416       cyclopentanecarboxoyl    71 1-adamantaneacetoyl                       40.50 (l)                              385.48                                   (ND)    72 1-naphthylacetoyl                       3.90 (s)                              377.42                                   (ND)    73 1-napthoyl      3.64 (s)                              363.39                                   363.8    74 1-phenyl-1-cyclopropanecarboxoyl                       38.07 (l)                              353.4                                   (ND)    75 4-iodobenzoyl   3.79 (s)                              439.23                                   (ND)    76 4-isopropoxybenzoyl                       4.38 (s)                              371.41                                   (ND)    77 2,3-dichlorobenzoyl                       35.78 (l)                              382.22                                   (ND)    78 4-methoxyphenylacetoyl                       3.94 (s)                              357.39                                   (ND)    79 2,3-dimethoxybenzoyl                       3.61 (s)                              373.39                                   (ND)    80 2,4-dichlorobenzoyl                       36.44 (l)                              382.22                                   (ND)    81 2,4-difluorobenzoyl                       3.40 (s)                              349.32                                   (ND)    82 4-methyl-1-cyclohexanecarboxoyl                       3.21 (s)                              333.41                                   (ND)    83 2,4-dimethoxybenzoyl                       33.78 (l)                              373.39                                   (ND)    84 2,4-dimethylbenzoyl                       3.78 (s)                              341.39                                   (ND)    85 2,4-hexadienoyl 3.42 (s)                              303.34                                   (ND)    86 2,5-dichlorobenzoyl                       3.82 (s)                              382.22                                   (ND)    87 2,5-dimethylbenzoyl                       3.76 (s)                              341.39                                   (ND)    88 2,6-dichlorobenzoyl                       3.58 (s)                              382.22                                   381.9    89 2,6-difluorobenzoyl                       3.35 (s)                              349.31                                   (ND)    90 4-methylcyclohexaneacetoyl                       3.84 (s)                              347.44                                   (ND)    91 2,6-dimethoxybenzoyl                       3.37 (s)                              373.39                                   (ND)    92 2-(trifluoromethyl)-cinnamoyl                       4.27 (s)                              407.37                                   (ND)    93 4-methylvaleroyl                       3.33 (s)                              307.37                                   (ND)    94 2-bromobenzoyl  3.52 (s)                              392.23                                   (ND)    95 2-chloro-4,5-difluorobenzoyl                       3.83 (s)                              383.76                                   (ND)    96 2-chloro-4-fluorophenylacetoyl                       3.70 (s)                              379.8                                   (ND)    97 2-chlorobenzoyl 3.47 (s)                              347.78                                   (ND)    98 2-ethoxybenzoyl 3.67 (s)                              357.39                                   (ND)    99 2-ethyl-2-Hexenoyl                       4.03 (s)                              333.41                                   (ND)    100       2-ethylbutyroyl 3.41 (s)                              307.37                                   (ND)    101       (±)-2-ethylhexanoyl                       3.99 (s)                              335.42                                   (ND)    102       2-fluorobenzoyl 3.47 (s)                              331.32                                   (ND)    103       2-furoyl        3.03 (s)                              303.29                                   (ND)    104       4-hydroxyquinoline-2-carboxyl                              380.38                                   (ND)    105       (±)-2-methylbutyroyl                       3.10 (s)                              293.34                                   (ND)    106       2-methylcyclopropane-carboxyl                       3.10 (s)                              291.33                                   (ND)    107       2-naphthylacetoyl                       3.91 (s)                              377.42                                   (ND)    108       2-napthoyl      3.78 (s)                              363.39                                   (ND)    109       2-norbornaneacetoyl                       3.86 (s)                              345.41                                   (ND)    110       2-phenylbutyroyl                       3.88 (s)                              355.41                                   (ND)    111       2-propylpentanoyl                       3.96 (s)                              335.42                                   (ND)    112       2-pyrazinecarboxoyl                       2.74 (s)                              315.31                                   (ND)    113       2-thiopheneacetoyl                       3.32 (s)                              333.38                                   (ND)    114       3,3,3-triphenylpropionoyl                       4.60 (s)                              493.59                                   (ND)    115       3,3-diphenylpropionoyl                       4.26 (s)                              417.51                                   (ND)    116       3,4,5-triethoxybenzoyl                       4.16 (s)                              445.51                                   (ND)    117       3,4,5-trimethoxybenzoyl                       3.45 (s)                              403.41                                   (ND)    118       3,4,5-trimethoxycinnamoyl                       3.69 (s)                              429.45                                   (ND)    119       3,4-dichlorobenzoyl                       4.17 (s)                              382.22                                   (ND)    120       3,4-dichlorophenylacetoyl                              396.61                                   (ND)    121       3,4-difluorobenzoyl                       3.71 (s)                              349.32                                   (ND)    122       4-imidazolecarboxoyl   303.3                                   (ND)    123       4-tert-butyl-cyclohexanecarboxoyl                       4.32 (s)                              375.49                                   375.9    124       3,4-dimethoxybenzoyl                       3.29 (s)                              373.41                                   (ND)    125       3,4-dimethylbenzoyl                       3.77 (s)                              341.39                                   (ND)    126       3,5,5-trimethylhexanoyl                       4.21 (s)                              349.45                                   (ND)    127       3,5-bis(trifluoromethyl)-benzoyl                       4.49 (s)                              449.33                                   (ND)    128       5-bromo-2-chlorobenzoyl                       3.65 (s)                              426.67                                   (ND)    129       5-bromonicotinoyl                       3.18 (s)                              393.22                                   (ND)    130       5-phenylvaleroyl                       3.80 (s)                              369.44                                   (ND)    131       3,5-dichlorobenzoyl                       4.18 (s)                              382.22                                   (ND)    132       6-chloronicotinoyl                       3.10 (s)                              348.77                                   (ND)    133       3,5-dimethoxybenzoyl   372.39                                   (ND)    134       3,5-dimethyl-p-anisoyl                       3.82 (s)                              371.41                                   (ND)    135       3,5-dimethylbenzoyl                       3.79 (s)                              341.39                                   (ND)    136       3-(2-methoxyphenyl)propionoyl                       3.53 (s)                              371.41                                   (ND)    137       3-(3,4,5-trimethoxyphenyl)-                       3.43 (s)                              431.47                                   (ND)       propionoyl    138       3,4,5-trimethoxyphenylacetoyl                       3.21 (s)                              417.44                                   (ND)    139       3-(3,4-dimethoxyphenyl)-propionoyl                       3.35 (s)                              401.44                                   (ND)    140       heptanoyl       3.61 (s)                              321.4                                   (ND)    141       3-benzoylpropionoyl                       3.52 (s)                              369.4                                   (ND)    142       3-bromobenzoyl  3.87 (s)                              392.23                                   (ND)    143       3-bromophenylacetoyl                       3.79 (s)                              406.26                                   (ND)    144       chromone-2-carboxyl                       3.29 (s)                              381.36                                   (ND)    145       5-methyl-2-pyrazinecarboxoyl                              329.34                                   (ND)    146       3-chlorobenzoyl 3.61 (s)                              347.78                                   (ND)    147       3-cyanobenzoyl  3.42 (s)                              338.34                                   (ND)    148       3-cyclopentylpropionoyl                       3.89 (s)                              333.41                                   (ND)    149       3-(dimethylamino)benzoyl                       2.58 (s)                              356.4                                   (ND)    150       3-fluoro-4-methylbenzoyl                       3.80 (s)                              345.35                                   (ND)    151       3-fluorobenzoyl 3.52 (s)                              331.32                                   (ND)    152       3-fluorophenylacetoyl                       3.50 (s)                              345.35                                   (ND)    153       6-methoxy-α-methyl-2-                              421.48                                   (ND)       napthaleneacetoyl    154       3-iodo-4-methylbenzoyl                       4.18 (s)                              453.26                                   (ND)    155       formyl                 237.24                                   (ND)    156       6-methylnicotinoyl     328.35                                   (ND)    157       1-isoquinolinecarboxoyl                       3.47 (s)                              364.35                                   (ND)    158       lauryl          4.98 (s)                              391.53                                   (ND)    159       3-methoxyphenylacetoyl                       3.25 (s)                              357.39                                   (ND)    160       3-methyl-2-thiophenecarboxoyl                       3.28 (s)                              333.39                                   (ND)    161       3-methylvaleroyl                       3.48 (s)                              307.37                                   (ND)    162       3-phenoxybenzoyl                       4.05 (s)                              405.43                                   (ND)    163       3-phenylbutyroyl                       3.57 (s)                              355.41                                   (ND)    164       3-thiopheneacetoyl                       3.15 (s)                              333.38                                   (ND)    165       4'-ethyl-4-biphenylcarboxoyl                              417.49                                   (ND)    166       4-(diethylamino)benzoyl                       2.76 (s)                              384.45                                   (ND)    167       4-benzoylbenzoyl                       3.79 (s)                              417.44                                   (ND)    168       4-biphenylacetoyl                       3.91 (s)                              403.46                                   (ND)    169       4-biphenylcarboxoyl                       4.01 (s)                              389.41                                   (ND)    170       4-bromobenzoyl  3.61 (s)                              392.23                                   (ND)    171       4-bromophenylacetoyl                       3.56 (s)                              406.26                                   (ND)    172       4-butylbenzoyl  4.20 (s)                              369.44                                   (ND)    173       4-chloro-o-anisoyl                       3.71 (s)                              377.8                                   (ND)    174       4-chlorobenzoyl 3.53 (s)                              347.78                                   (ND)    __________________________________________________________________________

3. Reduction of the Mixtures of Resin-Bound L or D N-Acylatedp-nitrophenylalanine

All of the tea-bags from the previous step were placed in a largecontainer shaken with a solution of SnCl₂.2H₂ O in DMF (2.0 M, 1.5 L) atroom temperature overnight (˜16 hrs). The packets were washed with DMF(3×), methanol (2×) DCM (2×), air-dried for 30 min and then dried undervacuum for 1-2 hrs. The bags were sorted into appropriate sets for usein the subsequent chemistry.

4. Production and Cleavage of the Mixtures of Resin-Bound L or DN-Acylated p-phenylalanine with Aldehydes and Cyclopentadiene

Following the procedure in Example 1 nine 30-mg tea-bags (L or D Seriesof 4 sets of acid mixtures, and 1 sibling bag containing L-N-propylp-aminophenylalanine) were added to each solution of 25 aldehydes (1 M)in DMF (15 mL) and cooled in freezer (-10° C.) for 15-30 minutes. Aftercooling, 2.5 mL of cyclopentadiene (2M final concentration) was addedand the solution cooled in the freezer again for 15-30 minutes. Then1.16 mL of trifluoroacetic (1M) was added and the cyclization reactionshaken for 45-50 hours at room temperature. Following completion of thetricylic tetrahydroquinoline formation, the resin packets were washedwith DCM (2×), DMF (2×), and DCM (1×), MeOH (1×) and dried under vacuum.

The tricyclic tetrahydroquinoline controls (L-N-propylp-aminophenylalanine sibling bags) and mixtures were cleaved off theresin by treatment with HF (liquid (1)) at -15 ° C. for 2 hrs in thepresence of anisole followed by warming to room temperature whileremoving HF (gaseous (g)) with a nitrogen stream.

                  TABLE 4    ______________________________________    Experimental Data for Tricylic Tetrahydroquinoline Controls                             HPLC RT                             (5 cm    Yield Yield    No.  2-Substituent (R.sup.2)                             column)  (mg)  (%)    ______________________________________    1    carboxy             2.06     8.2   86    2    1-napthyl           4.29     8.1   72    3    2,3,4-trifluorophenyl                             4.31     9.7   86    4    2,3,5-trichlorophenyl                             4.94     8.1   64    5    2,3-difluorophenyl  4.15     11.2  103    6    2,4-dichlorophenyl  4.67     10    86    7    2,5-difluorophenyl  4.17     10    92    8    2,5-dimethylphenyl  4.13     8.9   84    9    2,6-difluorophenyl  3.64     9.8   90    10   2-bromophenyl       4.37     11.9  100    11   2-chloro-5-nitrophenyl                             4.24     7     59    12   2-fluorophenyl      3.94     9.5   91    13   3,4-(methylenedioxy)-6-nitrophenyl                             4        10.9  89    14   3,4-difluorophenyl  4.14     9.9   91    15   3,5-bis(trifluoromethyl)phenyl                             4.81     11.9  89    16   3,5-dichlorophenyl  4.7      13.1  112    17   3-cyanophenyl       3.83     13    123    18   3-fluorophenyl      4        11.4  110    19   3-formylchromone    3.74     11.4  98    20   3-nitro-4-chlorophenyl                             4.26     13    109    21   3-phenoxyphenyl     4.57     10.9  89    22   4-cyanophenyl       4.97     6.3   60    23   4-pyridinecarboxaldehyde                             0.33     9.6   96    24   3-methoxy-2-nitrophenyl                             3.82     11.9  100    25   3-hydroxy-4-nitrophenyl                             3.64     12.2  106    ______________________________________

All journal article and reference citations provided above, inparentheses or otherwise, whether previously stated or not, areincorporated herein by reference.

Although the invention has been described with reference to the examplesprovided above, it should be understood that various modifications canbe made by those skilled in the art without departing from theinvention. Accordingly, the invention is set out in the followingclaims.

We claim:
 1. A combinatorial library of two or more tricyclictetrahydroquinoline compounds of the formula:wherein in the aboveFormula I: ##STR6## R¹ is absent or present and, when present, isselected from the group consisting of C₁ to C₁₀ alkylene, C₁ to C₁₀substituted alkylene, C₂ to C₁₀ alkenyl, C₂ to C₁₀ substituted alkenyl,C₂ to C₁₀ alkynyl, C₂ to C₁₀ substituted alkynyl, C₃ to C₇ cycloalkyl,C₃ to C₇ substituted cycloalkyl, C₅ to C₇ cycloalkenyl, C₅ to C₇substituted cycloalkenyl, phenylene, substituted phenylene, naphthyl,substituted naphthyl, C₇ to C₁₂ phenylalkyl, C₇ to C₁₂ substitutedphenylalkyl, heterocyclic ring, substituted heterocyclic ring,heteroaryl ring, substituted heteroaryl ring, amino,(monosubstituted)amino, a group of the formula: --CH₂ C(O)NH-- and agroup of the formula:

    --(CH.sub.2).sub.p --Ar--(CH.sub.2).sub.q --

wherein p and q are independently selected from a number 0 to 6, whereinboth are not 0; and Ar is an aryl group selected from the groupconsisting of phenyl, substituted phenyl, heteroaryl ring andsubstituted heteroaryl ring; R², R³, and R⁴ are, independently, selectedfrom the group consisting of a hydrogen atom, halo, hydroxy, protectedhydroxy, cyano, nitro, C₁ to C₁₀ alkyl, C₂ to C₁₀ alkenyl, C₂ to C₁₀alkynyl, C₁ to C₁₀ substituted alkyl, C₂ to C₁₀ substituted alkenyl, C₂to C₁₀ substituted alkynyl, C₁ to C₇ alkoxy, C₁ to C₇ substitutedalkoxy, C₁ to C₇ acyloxy, C₁ to C₇ acyl, C₃ to C₇ cycloalkyl, C₃ to C₇substituted cycloalkyl, C₅ to C₇ cycloalkenyl, C₅ to C₇ substitutedcycloalkenyl, a heterocyclic ring, substituted heterocyclic ring, C₇ toC₁₂ phenylalkyl, C₇ to C₁₂ substituted phenylalkyl, phenyl, substitutedphenyl, naphthyl, substituted naphthyl, cyclic C₂ to C₇ alkylene,substituted cyclic C₂ to C₇ alkylene, cyclic C₂ to C₇ heteroalkylene,substituted cyclic C₂ to C₇ heteroalkylene, carboxy, protected carboxy,hydroxymethyl, protected hydroxymethyl, amino, protected amino,(monosubstituted)amino, protected (monosubstituted)amino,(disubstituted)amino, carboxamide, protected carboxamide, C₁ to C₄alkylthio, C₁ to C₄ substituted alkylthio, C₁ to C₄ alkylsulfonyl, C₁ toC₄ substituted alkylsulfonyl, C₁ to C₄ alkylsulfoxide, C₁ to C₄substituted alkylsulfoxide, phenylthio, substituted phenylthio,phenylsulfoxide, substituted phenylsulfoxide, phenylsulfonyl andsubstituted phenylsulfonyl; R⁵ is selected from the group consisting ofhydrogen, C₁ to C₁₀ alkyl, C₁ to C₁₀ substituted alkyl, C₂ to C₁₀alkenyl, C₂ to C₁₀ substituted alkenyl, C₂ to C₁₀ alkynyl, C₂ to C₁₀substituted alkynyl, C₃ to C₇ cycloalkyl, C₃ to C₇ substitutedcycloalkyl, C₅ to C₇ cycloalkenyl, C₅ to C₇ substituted cycloalkenyl,phenyl, substituted phenyl, naphthyl, substituted naphthyl, C₇ to C₁₂phenylalkyl, C₇ to C₁₂ substituted phenylalkyl, carboxy, protectedcarboxy, C₁ to C₇ acyl, C₁ to C₇ substituted acyl, heterocyclic ring,substituted heterocyclic ring, heteroaryl ring and substitutedheteroaryl ring; p0 R⁶ is selected from the group consisting of ahydrogen atom, C₁ to C₁₀ alkyl, C₁ to C₁₀ substituted alkyl, C₇ to C₁₂phenylalkyl, C₇ to C₁₂ substituted phenylalkyl, C₁ to C₇ acyl, C₁ to C₇substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, C₁ to C₄alkylsulfonyl, C₁ to C₄ substituted alkylsulfonyl, C₁ to C₆alkylaminocarbonyl, C₁ to C₆ substituted alkylaminocarbonyl,phenylaminocarbonyl, and substituted phenylaminocarbonyl; n is 1 to 3;and Y is selected from the group consisting of CO₂ H, SH, NHR⁷,C(O)NHR⁷, CH₂ OH, CH₂ NH₂, and CH₂ NHR⁷, wherein R⁷ is selected from thegroup consisting of a hydrogen atom, C₁ to C₁₀ alkyl, C₁ to C₁₀substituted alkyl, and a functionalized resin, providing that when Y isCO₂ H that R¹ is not absent and R⁵ is not phenyl,or a salt of thetricyclic tetrahydroquinoline.
 2. The combinatorial library of claim 1,wherein:R¹ is absent or present and, when present, is selected from thegroup consisting of C₁ to C₆ alkylene, C₁ to C₆ substituted alkylene,phenylene, substituted phenylene, and a group of the formula: --CH₂C(O)NH--; R², R³, and R⁴ are, independently, selected from the groupconsisting of a hydrogen atom, halo, hydroxy, protected hydroxy, nitro,C₁ to C₁₀ alkyl, C₁ to C₇ alkoxy, and cyclic C₂ to C₇ alkylene; R⁵ isselected from the group consisting of a hydrogen atom, C₁ to C₁₀ alkyl,C₁ to C₁₀ substituted alkyl, C₂ to C₁₀ alkenyl, C₂ to C₁₀ substitutedalkenyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, C₃to C₇ cycloalkyl, C₃ to C₇ substituted cycloalkyl, C₇ to C₁₂phenylalkyl, C₇ to C₁₂ substituted phenylalkyl, C₅ to C₇ cylcoalkenyl,C₅ to C₇ substituted cycloalkenyl, a heterocyclic ring, substitutedheterocyclic ring, heteroaryl, substituted heteroaryl, C₁ to C₇ acyl, C₁to C₇ substituted acyl, carboxy, and protected carboxy; R⁶ is a hydrogenatom; n is 1 to 2; and Y is C(O)NHR⁷ wherein R⁷ is selected from thegroup consisting of a hydrogen atom and a functionalized resin.
 3. Thecombinatorial library of claim 1, wherein:R¹ is absent or present and,when present, is selected from the group consisting of --CH₂ C(O)NH--and --CH₂ CH(NHR⁸)--, wherein R⁸ is selected from the group consistingof a hydrogen atom, C₁ to C₁₀ alkyl, C₁ to C₁₀ substituted alkyl, C₂ toC₁₀ alkenyl, C₂ to C₁₀ substituted alkenyl, C₂ to C₁₀ alkynyl, C₂ to C₁₀substituted alkynyl, C₇ to C₁₂ phenylalkyl, C₇ to C₁₂ substitutedphenylalkyl, C₁ to C₇ acyl, C₁ to C₇ substituted acyl, aminocarbonyl,protected aminocarbonyl, (monosubstituted)aminocarbonyl, protected(monosubstitituted)aminocarbonyl, (disubstituted)aminocarbonyl, C₁ to C₇alkylsulfonyl, C₇ to C₁₂ phenylalkylsulfonyl, phenylsulfonyl, andsubstituted phenylsulfonyl; R², R³, and R⁴ are each, independently,selected from the group consisting of a hydrogen atom, hydroxy, nitro,halo, C₁ to C₁₀ alkyl, C₁ to C₆ alkoxy, and cyclic C₂ to C₇ alkylene; R⁵is selected from the group consisting of a hydrogen atom, carboxy, C₁ toC₁₀ alkyl, C₁ to C₁₀ substituted alkyl, C₂ to C₁₀ alkenyl, C₂ to C₁₀substituted alkenyl, C₃ to C₈ cycloalkyl, phenyl, substituted phenyl,naphthyl, substituted naphthyl, heterocyclic ring, substitutedheterocyclic ring, heteroaryl ring and substituted heteroaryl ring; n isequal to 1; R⁶ is a hydrogen atom; and Y is selected from the groupconsisting of C(O)NH₂ and C(O)NH bound to a functionalized resin.
 4. Thecombinatorial library of claim 1, wherein:R¹ is absent or --CH₂ NHCO--;R², R³, and R⁴ are each, independently, selected from the groupconsisting of a hydrogen atom, hydroxy, fluoro, chloro, bromo, iodo,methyl, methoxy, nitro and --CH═CH--CH═CH-- fused to adjacent positions;R⁵ is selected from the group consisting of a hydrogen atom, phenyl,chloromethyl, cyclohexanyl, d,1-1,2-(dihydroxy)ethyl, carboxy, acetyl,2-hydroxyphenyl, tribromomethyl, trimethylacetyl, 1-methyl-2-pyrrolyl,1-napthyl, 2,3,4-trifluorophenyl, 2,3,5-trichlorophenyl,2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-difluorophenyl,2,5-dimethylphenyl, 2,6-difluorophenyl, 2-bromophenyl,2-chloro-nitrophenyl, 2-chloro-6-fluorophenyl, 2-cyanophenyl,2-ethylbutyryl, 2-fluorophenyl, 2-(2-oxymethylenecarboxy)phenyl,2-methoxy-1-naphthyl, 2-nitro-5-chlorophenyl, 2-nitrophenyl,2-pyridinyl, 3,4-(methylenedioxy)-6-nitrophenyl, 3,4-difluorophenyl,3,5-bis(trifluoromethyl)phenyl, 3,5-dichlorophenyl,3-(3,4-dichlorophenoxy)phenyl, 3-bromo-4-fluorophenyl, 3-bromophenyl,3-carboxyphenyl, 3-cyanophenyl, 3-fluorophenyl, 3-chromonyl, 3-furyl,3-hydroxyphenyl, 3-nitro-4-chlorophenyl, 3-nitrophenyl, 3-phenoxyphenyl,2-phenylpropyl, 3-pyridinyl, 4-bromo-2-thiophene-yl, 4-bromophenyl,4-carboxyphenyl, 4-cyanophenyl, 4-fluorophenyl, 4-nitrophenyl,4-pyridinyl, 4-quinolinyl, 5-bromo-2-hydroxyphenyl, 5-nitro-2-furyl,5-norbornene-2-yl, 6-methyl-2-pyridinyl, 9-ethyl-3-carbazolyl,1,2-dimethylbutyryl, 1,1-dimethyl-3-butenyl, 3-methoxy-2-nitro-phenyl,3-hydroxy-4-nitrophenyl, 1-methylpropyl, 1-methylbutyl,4-chloro-3-nitrophenyl, 4-(trifluoromethyl)phenyl, 1-methyldecanyl, andβ-phenylcinnaminyl; R⁶ is a hydrogen atom; n is 1; and Y is selectedfrom the group consisting of C(O)NH₂ and C(O)NH bound to afunctionalized resin.
 5. The combinatorial library of claim 1,wherein:R¹ is CH₂ CH(NHR⁸), wherein R⁸ is selected from the groupconsisting of acetyl, butyryl, cyclobutanecarbonyl,cycloheptanecarbonyl, 4-cyclohexanebutyryl, cyclohexanecarbonyl,3-cyclohexanepropionyl, cyclohexylacetyl, cyclopentanecarbonyl,cyclopentylacetyl, hydrocinnamyl, isobutyryl, isovaleryl, octanoyl,propionyl, tert-butylacetyl, trimethylacetyl, 1-adamantaneacetyl,4-methyl-1-cyclohexanecarbonyl, 4-methylcyclohexaneacetyl,4-methylvaleryl, 2-ethyl-2-hexenoyl, 2-ethylbutyryl, 2-ethylhexanoyl,2-methylbutyryl, 2-methylcyclopropanecarbonyl, 2-norbornaneacetyl,2-phenylbutyryl, 2-propylpentanoyl, 3,3,3-triphenylpropionyl,3,3-diphenylpropionyl, 4-tert-butyl-cyclohexanecarbonyl,3,5,5-trimethylhexanoyl, 5-phenylvaleryl, 3-(2-methoxyphenyl)propionyl,3-(3,4,5-trimethoxyphenyl)propionyl, 3-(3,4-dimethoxyphenyl)propionyl,heptanoyl, 3-cyclopentylpropionyl, formyl, lauryl, 3-methylvaleryl,3-phenylbutyryl, α-cyclohexylphenylacetyl, α-methylcinnamyl, crotonyl,ethoxyacetyl, 4-chlorocinnamyl, 4-ethoxyphenylacetyl, m-tolylacetyl,methoxyacetyl, p-tolylacetyl, phenoxyacetyl, phenylacetyl, tiglyl,trans-3-hexenoyl, trans-cinnamyl, trans-styrylacetyl, triphenylacetyl,4-fluorophenylacetyl, vinylacetyl, (2,5-dimethoxyphenyl)acetyl,(2-naphthoxy)acetyl, (3,4-dimethoxyphenyl)acetyl,(α-α-α-trifluoro-m-tolyl)acetyl, (methylthio)acetyl,1-(4-chlorophenyl)-1-cyclopentanecarbonyl, 1-naphthylacetyl,1-phenyl-1-cyclopropanecarbonyl, 4-isobutyl-α-methylphenylacetyl,4-methoxyphenylacetyl, 2,4-hexadienoyl, 2-(trifluoromethyl)-cinnamyl,2-chloro-4-fluorophenylacetyl, 2-naphthylacetyl,3,4,5-trimethoxycinnamyl, 3,4-dichlorophenylacetyl, 3,4-dimethylbenzoyl,3,4,5-trimethoxyphenylacetyl, 3-benzoylpropionyl, 3-bromophenylacetyl,3-fluorophenylacetyl, 3-methoxyphenylacetyl, 3-thiopheneacetyl,4-biphenylacetyl, 4-bromophenylacetyl, α,α,α-trifluoro-m-toluyl,α,α,α-trifluoro-o-toluyl, benzoyl, niflumyl, o-anisyl, o-toluyl,piperonylyl, 1-napthoyl, 2,3-dichlorobenzoyl, 2,3-dimethoxybenzoyl,2,4-dichlorobenzoyl, 2,4-difluorobenzoyl, 2,4-dimethoxybenzoyl,2,4-dimethylbenzoyl, 2,5-dichlorobenzoyl, 2,5-dimethylbenzoyl,2,6-dychlorobenzoyl, 2,6-difluorobenzoyl, 2,6-dimethoxybenzoyl,2-bromobenzoyl, 2-chloro-4,5-difluorobenzoyl, 2-chlorobenzoyl,2-ethoxybenzoyl, 2-fluorobenzoyl, 2-napthoyl, 3,4,5-triethoxybenzoyl,3,4,5-trimethoxybenzoyl, 3,4-dichlorobenzoyl, 3,4-difluorobenzoyl,3,4-dimethoxybenzoyl, 3,5-bis(trifluoromethyl)benzoyl,5-bromo-2-chlorobenzoyl, 3,5-dimethyl-p-anisyl, 3-bromobenzoyl,3-chlorobenzoyl, 3-cyanobenzoyl, 3-(dimethylamino)benzoyl,3-fluoro-4-methylbenzoyl, 3-fluorobenzoyl, 3-iodo-4-methylbenzoyl,3-phenoxybenzoyl, 4-chloro-o-anisyl, α,α,α-trifluoro-p-toluyl,4-cyanobenzoyl, 4-(dimethylamino)benzoyl, 4-ethoxybenzoyl, isonicotinyl,4-ethylbenzoyl, m-anisyl, m-toluyl, nicotinyl, p-anisyl, p-toluyl,picolinyl, pyrrole-2-carbonyl, 4-fluorobenzoyl, 4-isopropoxybenzoyl,tetrahydro-2-furoyl, tetrahydro-3-furoyl, trans-3-(3-pyridyl)acrylyl,xanthene-9-carbonyl, (4-pyridylthio)acetyl, (phenylthio)acetyl,4-iodobenzoyl, 4-isopropylbenzoyl, 2-furoyl, 2-pyrazinecarbonyl,2-thiopheneacetyl, 2-thiophenecarbonyl, 5-bromonicotinyl,3,5-dichlorobenzoyl, 6-chloronicotinyl, 3,5-dimethoxybenzoyl,3,5-dimethylbenzoyl, chromone-2-carbonyl, 1-isoquinolinecarbonyl,3-methyl-2-thiophene-yl, 4'-ethyl-4-biphenylcarbonyl,4-(diethylamino)benzoyl, 4-benzoylbenzoyl, 4-biphenylcarbonyl,4-bromobenzoyl, 4-butylbenzoyl, and 4-chlorobenzoyl; R², R³, and R⁴ areeach, independently, a hydrogen atom; R⁵ is selected from the groupconsisting of carboxy, 1-napthyl, 2,3,4-trifluorophenyl,2,3,5-trichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl,2,5-difluorophenyl, 2,5-dimethylphenyl, 2,6-difluorophenyl,2-bromophenyl, 2-chloro-5-nitrophenyl, 2-fluorophenyl,3,4-(methylenedioxy)-6-nitrophenyl, 3,4-difluorophenyl,3,5-bis(trifluoromethyl)phenyl, 3,5-dichlorophenyl, 3-cyanophenyl,3-fluorophenyl, 3-chromonyl, 3-nitro-4-chlorophenyl, 3-phenoxyphenyl,4-cyanophenyl, 4-pyridinyl, 3-methoxy-2-nitrophenyl, and3-hydroxy-4-nitrophenyl; R⁶ is a hydrogen atom; n is 1; and Y isselected from the group consisting of C(O)NH₂ and C(O)NH bound to afunctionalized resin.
 6. The combinatorial library of claim 1,wherein:R¹ is absent or present and, when present, is selected from thegroup consisting of --CH₂ NHCO-- and CH₂ CH(NHR⁸) wherein R⁸ is selectedfrom the group consisting of acetyl, butyryl, cyclobutanecarbonyl,cycloheptanecarbonyl, 4-cyclohexanebutyryl, cyclohexanecarbonyl,3-cyclohexanepropionyl, cyclohexylacetyl, cyclopentanecarbonyl,cyclopentylacetyl, hydrocinnamyl, isobutyryl, isovaleryl, octanoyl,propionyl, tert-butylacetyl, trimethylacetyl, 1-adamantaneacetyl,4-methyl-1-cyclohexanecarbonyl, 4-methylcyclohexaneacetyl,4-methylvaleryl, 2-ethyl-2-hexenoyl, 2-ethylbutyryl, 2-ethylhexanoyl,2-methylbutyryl, 2-methylcyclopropanecarbonyl, 2-norbornaneacetyl,2-phenylbutyryl, 2-propylpentanoyl, 3,3,3-triphenylpropionyl,3,3-diphenylpropionyl, 4-tert-butyl-cyclohexanecarbonyl,3,5,5-trimethylhexanoyl, 5-phenylvaleryl, 3-(2-methoxyphenyl)propionyl,3-(3,4,5-trimethoxyphenyl)propionyl, 3-(3,4-dimethoxyphenyl)propionyl,heptanoyl, 3-cyclopentylpropionyl, formyl, lauryl, 3-methylvaleryl,3-phenylbutyryl, α-cyclohexylphenylacetyl, α-methylcinnamyl, crotonyl,ethoxyacetyl, 4-chlorocinnamyl, 4-ethoxyphenylacetyl, m-tolylacetyl,methoxyacetyl, p-tolylacetyl, phenoxyacetyl, phenylacetyl, tiglyl,trans-3-hexenoyl, trans-cinnamyl, trans-styrylacetyl, triphenylacetyl,4-fluorophenylacetyl, vinylacetyl, (2,5-dimethoxyphenyl)acetyl,(2-naphthoxy)acetyl, (3,4-dimethoxyphenyl)acetyl,(α-α-α-trifluoro-m-tolyl)acetyl, (methylthio)acetyl,1-(4-chlorophenyl)-1-cyclopentanecarbonyl, 1-naphthylacetyl,1-phenyl-1-cyclopropanecarbonyl, 4-isobutyl-α-methylphenylacetyl,4-methoxyphenylacetyl, 2,4-hexadienoyl, 2-(trifluoromethyl)-cinnamyl,2-chloro-4-fluorophenylacetyl, 2-naphthylacetyl,3,4,5-trimethoxycinnamyl, 3,4-dichlorophenylacetyl, 3,4-dimethylbenzoyl,3,4,5-trimethoxyphenylacetyl, 3-benzoylpropionyl, 3-bromophenylacetyl,3-fluorophenylacetyl, 3-methoxyphenylacetyl, 3-thiopheneacetyl,4-biphenylacetyl, 4-bromophenylacetyl, α,α,α-trifluoro-m-toluyl,α,α,α-trifluoro-o-toluyl, benzoyl, niflumyl, o-anisyl, o-toluyl,piperonylyl, 1-napthoyl, 2,3-dichlorobenzoyl, 2,3-dimethoxybenzoyl,2,4-dichlorobenzoyl, 2,4-difluorobenzoyl, 2,4-dimethoxybenzoyl,2,4-dimethylbenzoyl, 2,5-dichlorobenzoyl, 2,5-dimethylbenzoyl,2,6-dychlorobenzoyl, 2,6-difluorobenzoyl, 2,6-dimethoxybenzoyl,2-bromobenzoyl, 2-chloro-4,5-difluorobenzoyl, 2-chlorobenzoyl,2-ethoxybenzoyl, 2-fluorobenzoyl, 2-napthoyl, 3,4,5-triethoxybenzoyl,3,4,5-trimethoxybenzoyl, 3,4-dichlorobenzoyl, 3,4-difluorobenzoyl,3,4-dimethoxybenzoyl, 3,5-bis(trifluoromethyl)benzoyl,5-bromo-2-chlorobenzoyl, 3,5-dimethyl-p-anisyl, 3-bromobenzoyl,3-chlorobenzoyl, 3-cyanobenzoyl, 3-(dimethylamino)benzoyl,3-fluoro-4-methylbenzoyl, 3-fluorobenzoyl, 3-iodo-4-methylbenzoyl,3-phenoxybenzoyl, 4-chloro-o-anisyl, α,α,α-trifluoro-p-toluyl,4-cyanobenzoyl, 4-(dimethylamino)benzoyl, 4-ethoxybenzoyl, isonicotinyl,4-ethylbenzoyl, m-anisyl, m-toluyl, nicotinyl, p-anisyl, p-toluyl,picolinyl, pyrrole-2-carbonyl, 4-fluorobenzoyl, 4-isopropoxybenzoyl,tetrahydro-2-furoyl, tetrahydro-3-furoyl, trans-3-(3-pyridyl)acrylyl,xanthene-9-carbonyl, (4-pyridylthio)acetyl, (phenylthio)acetyl,4-iodobenzoyl, 4-isopropylbenzoyl, 2-furoyl, 2-pyrazinecarbonyl,2-thiopheneacetyl, 2-thiophenecarbonyl, 5-bromonicotinyl,3,5-dichlorobenzoyl, 6-chloronicotinyl, 3,5-dimethoxybenzoyl,3,5-dimethylbenzoyl, chromone-2-carbonyl, 1-isoquinolinecarbonyl,3-methyl-2-thiophene-yl, 4'-ethyl-4-biphenylcarbonyl,4-(diethylamino)benzoyl, 4-benzoylbenzoyl, 4-biphenylcarbonyl,4-bromobenzoyl, 4-butylbenzoyl, and 4-chlorobenzoyl; R², R³, and R⁴ areeach, independently, selected from the group consisting of a hydrogenatom, hydroxy, fluoro, chloro, bromo, iodo, methyl, methoxy, nitro and--CH═CH--CH═CH-- fused to adjacent positions; R⁵ is selected from thegroup consisting of a hydrogen atom, phenyl, chloromethyl, cyclohexanyl,d,1-1,2-(dihydroxy)ethyl, carboxy, acetyl, 2-hydroxyphenyl,tribromomethyl, trimethylacetyl, 1-methyl-2-pyrrolyl, 1-napthyl,2,3,4-trifluorophenyl, 2,3,5-trichlorophenyl, 2,3-difluorophenyl,2,4-dichlorophenyl, 2,5-difluorophenyl, 2,5-dimethylphenyl,2,6-difluorophenyl, 2-bromophenyl, 2-chloro-5-nitrophenyl,2-chloro-6-fluorophenyl, 2-cyanophenyl, 2-ethylbutyryl, 2-fluorophenyl,2-(2-oxymethylenecarboxy)phenyl, 2-methoxy-1-naphthyl,2-nitro-5-chlorophenyl, 2-nitrophenyl, 2-pyridinyl,3,4-(methylenedioxy)-6-nitrophenyl, 3,4-difluorophenyl,3,5-bis(trifluoromethyl)phenyl, 3,5-dichlorophenyl,3-(3,4-dichlorophenoxy)phenyl, 3-bromo-4-fluorophenyl, 3-bromophenyl,3-carboxyphenyl, 3-cyanophenyl, 3-fluorophenyl, 3-chromonyl, 3-furyl,3-hydroxyphenyl, 3-nitro-4-chlorophenyl, 3-nitrophenyl, 3-phenoxyphenyl,2-phenylpropyl, 3-pyridinyl, 4-bromo-2-thiophene-yl, 4-bromophenyl,4-carboxyphenyl, 4-cyanophenyl, 4-fluorophenyl, 4-nitrophenyl,4-pyridinyl, 4-quinolinyl, 5-bromo-2-hydroxyphenyl, 5-nitro-2-furyl,5-norbornene-2-yl, 6-methyl-2-pyridinyl, 9-ethyl-3-carbazolyl,1,2-dimethylbutyryl, 1,1-dimethyl-3-butenyl, 3-methoxy-2-nitro-phenyl,3-hydroxy-4-nitrophenyl, 1-methylpropyl, 1-methylbutyl,4-chloro-3-nitrophenyl, 4-(trifluoromethyl)phenyl, 1-methyldecanyl, andβ-phenylcinnaminyl; R⁶ is selected from the group consisting ofnalidixoyl, 2-phenyl-4-quinolinecarboxy, 2-pyrazinecarboxy, niflumoyl,4-nitrophenylacetyl, 4-(4-nitrophenyl)butyroyl,(3,4-dimethoxyphenyl)-acetyl, 3,4-(methylenedioxy)phenylacetyl,4-nitrocinnamoyl, 3,4,-(methylenedioxy)cinnamoyl,3,4,5-trimethoxycinnamoyl, benzoyl, 2-chlorobenzoyl, 2-nitrobenzoyl,2-(p-toluoyl)benzoyl, 2,4-dinitrophenylacetyl,3-(3,4,5-trimethoxyphenyl)-propionyl, 4-biphenylacetyl, 1-napthylacetyl,(2-napthoxy)acetyl, trans-cinnamoyl, picolinyl,3-amino-4-hydroxybenzoyl, (4-pyridylthio)acetyl, 2,4-dichlorobenzoyl,3,4-dichlorobenzoyl, 4-biphenylcarboxy, thiophenoxyacetyl,1-benzoylpropionyl, phenylacetyl, hydrocinnamoyl, 3,3-diphenylpropionyl,3,3,3-triphenylpropionyl, 4-phenylbutyryl, phenoxyacetyl,(+/-)-2-phenoxypropionyl, 2,4-dimethoxybenzoyl, 3,4-dimethoxybenzoyl,3,4-dihydroxybenzoyl, 2,4-dihydroxybenzoyl, 3,4,5-trimethoxybenzoyl,3,4,5-triethoxybenzoyl, 3,4,5-trihydroxybenzoyl, 2-benzoylbenzoyl,1-napthoyl, xanthene-9-carboxy, 4-chloro-2-nitrobenzoyl,2-chloro-4-nitrobenzoyl, 4-chloro-3-nitrobenzoyl,2-chloro-5-nitrobenzoyl, 4-(dimethylamino)benzoyl,4-(diethylamino)benzoyl, 4-nitrobenzoyl, 3-(dimethylamino)benzoyl,p-methylbenzoyl, p-methoxybenzoyl, trimethylacetyl, tert-butylacetyl,(-)-menthoxyacetyl, cyclohexanecarboxy, cyclohexylacetyl,dicyclohexylacetyl, 4-cyclohexylbutyroyl, cycloheptanecarboxy,13-isopropylpodocarpa-7,13-dien-15-oyl, acetyl, octanoyl,(methylthio)acetyl, 3-nitropropionyl, 4-amino-3 hydroxybenzoyl,3-(2-methyl-4-nitro-1-imidizoyl)propionyl, 2-furoyl,(s)(-)-2-pyrrolidone-5-carboxy, (2-pyrimidylthio)acetyl,4-methoxy-2-quinolinecarboxy, 1-adamantanecarboxy, piperonoyl,5-methyl-3-phenylisoxazole-4-carboxy, rhodanine-3-acetyl,2-norbornaneacetyl, nicotinoyl, 9-oxo-9H-thioxanthene-3-carboxyl-10,10dioxide, 2-thiophenecarboxy, 5-nitro-2-furanoyl, indole-3-acetyl,isonicotinoyl, 3a-hydroxy-5β-cholan-24-oyl,(3α,7α,12α)-trihydroxy-5β-cholan-24-oyl, (3α, 5β-12α)-3,12,dihydroxy-5-cholan-24-oyl, (3α, 5β, 6α)-3,6-dihydroxy-cholan-24-oyl,L-alaninyl, L-cysteinyl, L-aspartinyl, L-glutaminyl, L-phenylalaninyl,glycinyl, L-histidinyl, L-isoleucinyl, L-lyscinyl, L-leucinyl,L-methionylsulfoxide, L-methionyl, L-asparginyl, L-prolinyl,L-glutaminyl, L-arganinyl, L-serinyl, L-threoninyl, L-valinyl,L-tryptophanoyl, L-tyrosinyl, D-alaninyl, D-cysteinyl, D-aspartinyl,D-glutaminyl, D-phenylalaninyl, glycinyl, D-histidinyl, D-isoleucinyl,D-lyscinyl, D-leucinyl, D-methionylsulfoxide, D-methionyl, D-asparginyl,D-prolinyl, D-glutaminyl, D-arganinyl, D-serinyl, D-threoninyl,D-valinyl, D-tryptophanoyl, D-tyrosinyl, 2-aminobutyroyl,4-aminobutyroyl, 2-aminoisobutyroyl, L-norleucinyl, D-norleucinyl,6-aminohexanoyl, 7-aminoheptanoyl, thioprolinyl, L-norvalinyl,D-norvalinyl, α-ornithinyl, methionyl sulfonyl, L-naphthylalaninyl,D-naphthylalaninyl, L-phenylglycinyl, D-phenylglycinyl, β-alaninyl,L-cyclohexylalaninyl, D-cyclohexylalaninyl, hydroxyprolinyl,4-nitrophenylalaninyl, dehydroprolinyl, 3-hydroxy-1-propanesulfonyl,1-propanesulfonyl, 1-octanesulfonyl, perfluoro-1-octanesulfonly,(+)-10-camphorsulfonyl, (-)-10-camphorsulfonyl, benzenesulfonyl,2-nitrobenzenesulfonyl, p-toluenesulfonyl, 4-nitrobenzenesulfonyl,n-acetylsulfanilyl, 2,5-dichlorobenzenesulfonyl,2,4-dinitrobenzenesulfonyl, 2-mesitylenesulfonyl and2-napthalenesulfonyl; n is 1; and Y is selected from the groupconsisting of C(O)NH₂ and C(O)NH bound to a functionalized resin.
 7. Thecombinatorial library of claim 1 where in the library is comprised ofplurality of mixtures of two or more of the tetrahydroquinolinecompounds of claim 1, wherein within each of the mixtures all thecompounds have at least one substituent in common, wherein thesubstituent is selected from the group consisting of R¹, R², R³, R⁴, R⁵,R⁶ and Y, with the proviso that not all of the substituents are incommon and that all other noncommon substituents are present asequimolar mixtures.
 8. A single tricyclic tetrahydroquinoline compoundof the formula: ##STR7## wherein in the above Formula I: R¹ is absent orpresent and, when present, is selected from the group consisting of C₁to C₁₀ alkylene, C₁ to C₁₀ substituted alkylene, C₂ to C₁₀ alkenyl, C₂to C₁₀ substituted alkenyl, C₂ to C₁₀ alkynyl, C₂ to C₁₀ substitutedalkynyl, C₃ to C₇ cycloalkyl, C₃ to C₇ substituted cycloalkyl, C₅ to C₇cycloalkenyl, C₅ to C₇ substituted cycloalkenyl, phenylene, substitutedphenylene, naphthyl, substituted naphthyl, C₇ to C₁₂ phenylalkyl, C₇ toC₁₂ substituted phenylalkyl, heterocyclic ring, substituted heterocyclicring, heteroaryl ring, substituted heteroaryl ring, amino,(monosubstituted)amino, a group of the formula: --CH₂ C(O)NH-- and agroup of the formula:

    --(CH.sub.2).sub.p --Ar--(CH.sub.2).sub.q --

wherein p and q are independently selected from a number 0 to 6, whereinboth are not 0; and Ar is an aryl group selected from the groupconsisting of phenyl, substituted phenyl, heteroaryl ring andsubstituted heteroaryl ring; R², R³, and R⁴ are, independently, selectedfrom the group consisting of a hydrogen atom, halo, hydroxy, protectedhydroxy, cyano, nitro, C₁ to C₁₀ alkyl, C₂ to C₁₀ alkenyl, C₂ to C₁₀alkynyl, C₁ to C₁₀ substituted alkyl, C₂ to C₁₀ substituted alkenyl, C₂to C₁₀ substituted alkynyl, C₁ to C₇ alkoxy, C₁ to C₇ substitutedalkoxy, C₁ to C₇ acyloxy, C₁ to C₇ acyl, C₃ to C₇ cycloalkyl, C₃ to C₇substituted cycloalkyl, C₅ to C₇ cycloalkenyl, C₅ to C₇ substitutedcycloalkenyl, a heterocyclic ring, substituted heterocyclic ring, C₇ toC₁₂ phenylalkyl, C₇ to C₁₂ substituted phenylalkyl, phenyl, substitutedphenyl, naphthyl, substituted naphthyl, cyclic C₂ to C₇ alkylene,substituted cyclic C₂ to C₇ alkylene, cyclic C₂ to C₇ heteroalkylene,substituted cyclic C₂ to C₇ heteroalkylene, carboxy, protected carboxy,hydroxymethyl, protected hydroxymethyl, amino, protected amino,(monosubstituted)amino, protected (monosubstituted)amino,(disubstituted)amino, carboxamide, protected carboxamide, C₁ to C₄alkylthio, C₁ to C₄ substituted alkylthio, C₁ to C₄ alkylsulfonyl, C₁ toC₄ substituted alkylsulfonyl, C₁ to C₄ alkylsulfoxide, C₁ to C₄substituted alkylsulfoxide, phenylthio, substituted phenylthio,phenylsulfoxide, substituted phenylsulfoxide, phenylsulfonyl andsubstituted phenylsulfonyl; R₅ is selected from the group consisting ofhydrogen, C₁ to C₁₀ alkyl, C₁ to C₁₀ substituted alkyl, C₂ to C₁₀alkenyl, C₂ to C₁₀ substituted alkenyl, C₂ to C₁₀ alkynyl, C₂ to C₁₀substituted alkynyl, C₃ to C₇ cycloalkyl, C₃ to C₇ substitutedcycloalkyl, C₅ to C₇ cycloalkenyl, C₅ to C₇ substituted cycloalkenyl,phenyl, substituted phenyl, naphthyl, substituted naphthyl, C₇ to C₁₂phenylalkyl, C₇ to C₁₂ substituted phenylalkyl, carboxy, protectedcarboxy, C₁ to C₇ acyl, C₇ to C₇ substituted acyl, heterocyclic ring,substituted heterocyclic ring, heteroaryl ring and substitutedheteroaryl ring; R⁶ is selected from the group consisting of a hydrogenatom, C₁ to C₁₀ alkyl, C₁ to C₁₀ substituted alkyl, C₇ to C₁₂phenylalkyl, C₇ to C₁₂ substituted phenylalkyl, C₁ to C₇ acyl, C₁ to C₇substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, C₁ to C₄alkylsulfonyl, C₁ to C₄ substituted alkylsulfonyl, C₁ to C₆alkylaminocarbonyl, C₁ to C₆ substituted alkylaminocarbonyl,phenylaminocarbonyl, and substituted phenylaminocarbonyl; n is 1 to 3;and Y is selected from the group consisting of CO₂ H, SH, NHR⁷,C(O)NHR⁷, CH₂ OH, CH₂ NH₂, and CH₂ NHR⁷, wherein R⁷ is selected from thegroup consisting of a hydrogen atom, C₁ to C₁₀ alkyl, and C₁ to C₁₀substituted alkyl, providing that when Y is CO₂ H that R¹ is not absentand R⁵ is not phenyl and that when Y is NHR⁷ that R⁷ is not a hydrogenatom,or a salt of the tricyclic tetrahydroquinoline.
 9. The singletricyclic tetrahydroquinoline compound of claim 8, wherein:R¹ is absentor present and, when present, is selected from the group consisting ofC₁ to C₆ alkylene, C₁ to C₆ substituted alkylene, phenylene, substitutedphenylene, and a group of the formula: --CH₂ C (O) NH--; R², R³, and R⁴are, independently, selected from the group consisting of a hydrogenatom, halo, hydroxy, protected hydroxy, nitro, C₁ to C₁₀ alkyl, C₁ to C₇alkoxy, and cyclic C₂ to C₇ alkylene; R⁵ is selected from the groupconsisting of a hydrogen atom, C₁ to C₁₀ alkyl, C₁ to C₁₀ substitutedalkyl, C₂ to C₁₀ alkenyl, C₂ to C₁₀ substituted alkenyl, phenyl,substituted phenyl, naphthyl, substituted naphthyl, C₃ to C₇ cycloalkyl,C₃ to C₇ substituted cycloalkyl, C₇ to C₁₂ phenylalkyl, C₇ to C₁₂substituted phenylalkyl, C₅ to C₇ cylcoalkenyl, C₅ to C₇ substitutedcycloalkenyl, a heterocyclic ring, substituted heterocyclic ring,heteroaryl, substituted heteroaryl, C₁ to C₇ acyl, C₁ to C₇ substitutedacyl, carboxy, and protected carboxy; R⁶ is a hydrogen atom; n is 1 to2; and Y is C(O)NH₂.
 10. The single tricyclic tetrahydroquinolinecompound of claim 8, wherein:R¹ is absent or present and, when present,is selected from the group consisting of --CH₂ C(O)NH-- and --CH₂CH(NHR⁸)--, wherein R⁸ is selected from the group consisting of ahydrogen atom, C₁ to C₁₀ alkyl, C₁ to C₁₀ substituted alkyl, C₂ to C₁₀alkenyl, C₂ to C₁₀ substituted alkenyl, C₂ to C₁₀ alkynyl, C₂ to C₁₀substituted alkynyl, C₇ to C₁₂ phenylalkyl, C₇ to C₁₂ substitutedphenylalkyl, C₁ to C₇ acyl, C₁ to C₇ substituted acyl, aminocarbonyl,protected aminocarbonyl, (monosubstituted)aminocarbonyl, protected(monosubstitituted)aminocarbonyl, (disubstituted)aminocarbonyl, C₁ to C₇alkylsulfonyl, C₇ to C₁₂ phenylalkylsulfonyl, phenylsulfonyl, andsubstituted phenylsulfonyl; R², R³, and R⁴ are each, independently,selected from the group consisting of a hydrogen atom, hydroxy, nitro,halo, C₁ to C₁₀ alkyl, C₁ to C₆ alkoxy, and cyclic C₂ to C₇ alkylene; R⁵is selected from the group consisting of a hydrogen atom, carboxy, C₁ toC₁₀ alkyl, C₁ to C₁₀ substituted alkyl, C₂ to C₁₀ alkenyl, C₂ to C₁₀substituted alkenyl, C₃ to C₈ cycloalkyl, phenyl, substituted phenyl,naphthyl, substituted naphthyl, heterocyclic ring, substitutedheterocyclic ring, heteroaryl ring and substituted heteroaryl ring; n isequal to 1; R⁶ is a hydrogen atom; and Y is C(O)NH₂.
 11. The singletricyclic tetrahydroquinoline compound of claim l, wherein:R' is absentor --CH₂ NHCO--; R², R³, and R⁴ are each, independently, selected fromthe group consisting of a hydrogen atom, hydroxy, fluoro, chloro, bromo,iodo, methyl, methoxy, nitro and --CH═CH--CH═CH-- fused to adjacentpositions; R⁵ is selected from the group consisting of a hydrogen atom,phenyl, chloromethyl, cyclohexanyl, d,1-1,2-(dihydroxy)ethyl, carboxy,acetyl, 2-hydroxyphenyl, tribromomethyl, trimethylacetyl,1-methyl-2-pyrrolyl, 1-napthyl, 2,3,4-trifluorophenyl,2,3,5-trichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl,2,5-difluorophenyl, 2,5-dimethylphenyl, 2,6-difluorophenyl,2-bromophenyl, 2-chloro-5-nitrophenyl, 2-chloro-6-fluorophenyl,2-cyanophenyl, 2-ethylbutyryl, 2-fluorophenyl,2-(2-oxymethylenecarboxy)phenyl, 2-methoxy-1-naphthyl,2-nitro-5-chlorophenyl, 2-nitrophenyl, 2-pyridinyl,3,4-(methylenedioxy)-6-nitrophenyl, 3,4-difluorophenyl,3,5-bis(trifluoromethyl)phenyl, 3,5-dichlorophenyl,3-(3,4-dichlorophenoxy)phenyl, 3-bromo-4-fluorophenyl, 3-bromophenyl,3-carboxyphenyl, 3-cyanophenyl, 3-fluorophenyl, 3-chromonyl, 3-furyl,3-hydroxyphenyl, 3-nitro-4-chlorophenyl, 3-nitrophenyl, 3-phenoxyphenyl,2-phenylpropyl, 3-pyridinyl, 4-bromo-2-thiophene-yl, 4-bromophenyl,4-carboxyphenyl, 4-cyanophenyl, 4-fluorophenyl, 4-nitrophenyl,4-pyridinyl, 4-quinolinyl, 5-bromo-2-hydroxyphenyl, 5-nitro-2-furyl,5-norbornene-2-yl, 6-methyl-2-pyridinyl, 9-ethyl-3-carbazolyl,1,2-dimethylbutyryl, 1,1-dimethyl-3-butenyl, 3-methoxy-2-nitro-phenyl,3-hydroxy-4-nitrophenyl, 1-methylpropyl, 1-methylbutyl,4-chloro-3-nitrophenyl, 4-(trifluoromethyl)phenyl, 1-methyldecanyl, andβ-phenylcinnaminyl; R⁶ is a hydrogen atom; n is 1; and Y is C(O)NH₂. 12.The single tricyclic tetrahydroquinoline compound of claim 8, wherein:R¹is CH₂ CH(NHR⁸), wherein R⁸ is selected from the group consisting ofacetyl, butyryl, cyclobutanecarbonyl, cycloheptanecarbonyl,4-cyclohexanebutyryl, cyclohexanecarbonyl, 3-cyclohexanepropionyl,cyclohexylacetyl, cyclopentanecarbonyl, cyclopentylacetyl,hydrocinnamyl, isobutyryl, isovaleryl, octanoyl, propionyl,tert-butylacetyl, trimethylacetyl, 1-adamantaneacetyl,4-methyl-1-cyclohexanecarbonyl, 4-methylcyclohexaneacetyl,4-methylvaleryl, 2-ethyl-2-hexenoyl, 2-ethylbutyryl, 2-ethylhexanoyl,2-methylbutyryl, 2-methylcyclopropanecarbonyl, 2-norbornaneacetyl,2-phenylbutyryl, 2-propylpentanoyl, 3,3,3-triphenylpropionyl,3,3-diphenylpropionyl, 4-tert-butyl-cyclohexanecarbonyl,3,5,5-trimethylhexanoyl, 5-phenylvaleryl, 3-(2-methoxyphenyl)propionyl,3-(3,4,5-trimethoxyphenyl)propionyl, 3-(3,4-dimethoxyphenyl)propionyl,heptanoyl, 3-cyclopentylpropionyl, formyl, lauryl, 3-methylvaleryl,3-phenylbutyryl, α-cyclohexylphenylacetyl, α-methylcinnamyl, crotonyl,ethoxyacetyl, 4-chlorocinnamyl, 4-ethoxyphenylacetyl, m-tolylacetyl,methoxyacetyl, p-tolylacetyl, phenoxyacetyl, phenylacetyl, tiglyl,trans-3-hexenoyl, trans-cinnamyl, trans-styrylacetyl, triphenylacetyl,4-fluorophenylacetyl, vinylacetyl, (2,5-dimethoxyphenyl)acetyl,(2-naphthoxy)acetyl, (3,4-dimethoxyphenyl)acetyl,(α-α-α-trifluoro-m-tolyl)acetyl, (methylthio)acetyl,1-(4-chlorophenyl)-1-cyclopentanecarbonyl, 1-naphthylacetyl,1-phenyl-1-cyclopropanecarbonyl, 4-isobutyl-α-methylphenylacetyl,4-methoxyphenylacetyl, 2,4-hexadienoyl, 2-(trifluoromethyl)-cinnamyl,2-chloro-4-fluorophenylacetyl, 2-naphthylacetyl,3,4,5-trimethoxycinnamyl, 3,4-dichlorophenylacetyl, 3,4-dimethylbenzoyl,3,4,5-trimethoxyphenylacetyl, 3-benzoylpropionyl, 3-bromophenylacetyl,3-fluorophenylacetyl, 3-methoxyphenylacetyl, 3-thiopheneacetyl,4-biphenylacetyl, 4-bromophenylacetyl, α,α,α-trifluoro-m-toluyl,α,α,α-trifluoro-o-toluyl, benzoyl, niflumyl, o-anisyl, o-toluyl,piperonylyl, 1-napthoyl, 2,3-dichlorobenzoyl, 2,3-dimethoxybenzoyl,2,4-dichlorobenzoyl, 2,4-difluorobenzoyl, 2,4-dimethoxybenzoyl,2,4-dimethylbenzoyl, 2,5-dichlorobenzoyl, 2,5-dimethylbenzoyl,2,6-dychlorobenzoyl, 2,6-difluorobenzoyl, 2,6-dimethoxybenzoyl,2-bromobenzoyl, 2-chloro-4,5-difluorobenzoyl, 2-chlorobenzoyl,2-ethoxybenzoyl, 2-fluorobenzoyl, 2-napthoyl, 3,4,5-triethoxybenzoyl,3,4,5-trimethoxybenzoyl, 3,4-dichlorobenzoyl, 3,4-difluorobenzoyl,3,4-dimethoxybenzoyl, 3,5-bis(trifluoromethyl)benzoyl,5-bromo-2-chlorobenzoyl, 3,5-dimethyl-p-anisyl, 3-bromobenzoyl,3-chlorobenzoyl, 3-cyanobenzoyl, 3-(dimethylamino)benzoyl,3-fluoro-4-methylbenzoyl, 3-fluorobenzoyl, 3-iodo-4-methylbenzoyl,3-phenoxybenzoyl, 4-chloro-o-anisyl, α,α,α-trifluoro-p-toluyl,4-cyanobenzoyl, 4-(dimethylamino)benzoyl, 4-ethoxybenzoyl, isonicotinyl,4-ethylbenzoyl, m-anisyl, m-toluyl, nicotinyl, p-anisyl, p-toluyl,picolinyl, pyrrole-2-carbonyl, 4-fluorobenzoyl, 4-isopropoxybenzoyl,tetrahydro-2-furoyl, tetrahydro-3-furoyl, trans-3-(3-pyridyl)acrylyl,xanthene-9-carbonyl, (4-pyridylthio)acetyl, (phenylthio)acetyl,4-iodobenzoyl, 4-isopropylbenzoyl, 2-furoyl, 2-pyrazinecarbonyl,2-thiopheneacetyl, 2-thiophenecarbonyl, 5-bromonicotinyl,3,5-dichlorobenzoyl, 6-chloronicotinyl, 3,5-dimethoxybenzoyl,3,5-dimethylbenzoyl, chromone-2-carbonyl, 1-isoquinolinecarbonyl,3-methyl-2-thiophene-yl, 4'-ethyl-4-biphenylcarbonyl,4-(diethylamino)benzoyl, 4-benzoylbenzoyl, 4-biphenylcarbonyl,4-bromobenzoyl, 4-butylbenzoyl, and 4-chlorobenzoyl; R², R³, and R⁴ areeach, independently, a hydrogen atom; R⁵ is selected from the groupconsisting of carboxy, 1-napthyl, 2,3,4-trifluorophenyl,2,3,5-trichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl,2,5-difluorophenyl, 2,5-dimethylphenyl, 2,6-difluorophenyl,2-bromophenyl, 2-chloro-5-nitrophenyl, 2-fluorophenyl,3,4-(methylenedioxy)-6-nitrophenyl, 3,4-difluorophenyl,3,5-bis(trifluoromethyl)phenyl, 3,5-dichlorophenyl, 3-cyanophenyl,3-fluorophenyl, 3-chromonyl, 3-nitro-4-chlorophenyl, 3-phenoxyphenyl,4-cyanophenyl, 4-pyridinyl, 3-methoxy-2-nitrophenyl, and3-hydroxy-4-nitrophenyl; R⁶ is a hydrogen atom; n is 1; and Y is C (O)NH₂.
 13. The single tricyclic tetrahydroquinoline compound of claim 8,wherein:R¹ is absent or present and, when present, is selected from thegroup consisting of --CH₂ NHCO-- and CH₂ CH(NHR⁸) wherein R⁸ is selectedfrom the group consisting of acetyl, butyryl, cyclobutanecarbonyl,cycloheptanecarbonyl, 4-cyclohexanebutyryl, cyclohexanecarbonyl,3-cyclohexanepropionyl, cyclohexylacetyl, cyclopentanecarbonyl,cyclopentylacetyl, hydrocinnamyl, isobutyryl, isovaleryl, octanoyl,propionyl, tert-butylacetyl, trimethylacetyl, 1-adamantaneacetyl,4-methyl-1-cyclohexanecarbonyl, 4-methylcyclohexaneacetyl,4-methylvaleryl, 2-ethyl-2-hexenoyl, 2-ethylbutyryl, 2-ethylhexanoyl,2-methylbutyryl, 2-methylcyclopropanecarbonyl, 2-norbornaneacetyl,2-phenylbutyryl, 2-propylpentanoyl, 3,3,3-triphenylpropionyl,3,3-diphenylpropionyl, 4-tert-butyl-cyclohexanecarbonyl,3,5,5-trimethylhexanoyl, 5-phenylvaleryl, 3-(2-methoxyphenyl)propionyl,3-(3,4,5-trimethoxyphenyl)propionyl, 3-(3,4-dimethoxyphenyl)propionyl,heptanoyl, 3-cyclopentylpropionyl, formyl, lauryl, 3-methylvaleryl,3-phenylbutyryl, α-cyclohexylphenylacetyl, α-methylcinnamyl, crotonyl,ethoxyacetyl, 4-chlorocinnamyl, 4-ethoxyphenylacetyl, m-tolylacetyl,methoxyacetyl, p-tolylacetyl, phenoxyacetyl, phenylacetyl, tiglyl,trans-3-hexenoyl, trans-cinnamyl, trans-styrylacetyl, triphenylacetyl,4-fluorophenylacetyl, vinylacetyl, (2,5-dimethoxyphenyl)acetyl,(2-naphthoxy)acetyl, (3,4-dimethoxyphenyl)acetyl,(α-α-α-trifluoro-m-tolyl)acetyl, (methylthio)acetyl,1-(4-chlorophenyl)-1-cyclopentanecarbonyl, 1-naphthylacetyl,1-phenyl-1-cyclopropanecarbonyl, 4-isobutyl-α-methylphenylacetyl,4-methoxyphenylacetyl, 2,4-hexadienoyl, 2-(trifluoromethyl)-cinnamyl,2-chloro-4-fluorophenylacetyl, 2-naphthylacetyl,3,4,5-trimethoxycinnamyl, 3,4-dichlorophenylacetyl, 3,4-dimethylbenzoyl,3,4,5-trimethoxyphenylacetyl, 3-benzoylpropionyl, 3-bromophenylacetyl,3-fluorophenylacetyl, 3-methoxyphenylacetyl, 3-thiopheneacetyl,4-biphenylacetyl, 4-bromophenylacetyl, α,α,α-trifluoro-m-toluyl,α,α,α-trifluoro-o-toluyl, benzoyl, niflumyl, o-anisyl, o-toluyl,piperonylyl, 1-napthoyl, 2,3-dichlorobenzoyl, 2,3-dimethoxybenzoyl,2,4-dichlorobenzoyl, 2,4-difluorobenzoyl, 2,4-dimethoxybenzoyl,2,4-dimethylbenzoyl, 2,5-dichlorobenzoyl, 2,5-dimethylbenzoyl,2,6-dychlorobenzoyl, 2,6-difluorobenzoyl, 2,6-dimethoxybenzoyl,2-bromobenzoyl, 2-chloro-4,5-difluorobenzoyl, 2-chlorobenzoyl,2-ethoxybenzoyl, 2-fluorobenzoyl, 2-napthoyl, 3,4,5-triethoxybenzoyl,3,4,5-trimethoxybenzoyl, 3,4-dichlorobenzoyl, 3,4-difluorobenzoyl,3,4-dimethoxybenzoyl, 3,5-bis(trifluoromethyl)benzoyl,5-bromo-2-chlorobenzoyl, 3,5-dimethyl-p-anisyl, 3-bromobenzoyl,3-chlorobenzoyl, 3-cyanobenzoyl, 3-(dimethylamino)benzoyl,3-fluoro-4-methylbenzoyl, 3-fluorobenzoyl, 3-iodo-4-methylbenzoyl,3-phenoxybenzoyl, 4-chloro-o-anisyl, α,α,α-trifluoro-p-toluyl,4-cyanobenzoyl, 4-(dimethylamino)benzoyl, 4-ethoxybenzoyl, isonicotinyl,4-ethylbenzoyl, m-anisyl, m-toluyl, nicotinyl, p-anisyl, p-toluyl,picolinyl, pyrrole-2-carbonyl, 4-fluorobenzoyl, 4-isopropoxybenzoyl,tetrahydro-2-furoyl, tetrahydro-3-furoyl, trans-3-(3-pyridyl)acrylyl,xanthene-9-carbonyl, (4-pyridylthio)acetyl, (phenylthio)acetyl,4-iodobenzoyl, 4-isopropylbenzoyl, 2-furoyl, 2-pyrazinecarbonyl,2-thiopheneacetyl, 2-thiophenecarbonyl, 5-bromonicotinyl,3,5-dichlorobenzoyl, 6-chloronicotinyl, 3,5-dimethoxybenzoyl,3,5-dimethylbenzoyl, chromone-2-carbonyl, 1-isoquinolinecarbonyl,3-methyl-2-thiophene-yl, 4'-ethyl-4-biphenylcarbonyl,4-(diethylamino)benzoyl, 4-benzoylbenzoyl, 4-biphenylcarbonyl,4-bromobenzoyl, 4-butylbenzoyl, and 4-chlorobenzoyl; R², R³, and R⁴ areeach, independently, selected from the group consisting of a hydrogenatom, hydroxy, fluoro, chloro, bromo, iodo, methyl, methoxy, nitro and--CH═CH--CH═CH-- fused to adjacent positions; R⁵ is selected from thegroup consisting of a hydrogen atom, phenyl, chloromethyl, cyclohexanyl,d,1-1,2-(dihydroxy)ethyl, carboxy, acetyl, 2-hydroxyphenyl,tribromomethyl, trimethylacetyl, 1-methyl-2-pyrrolyl, 1-napthyl,2,3,4-trifluorophenyl, 2,3,5-trichlorophenyl, 2,3-difluorophenyl,2,4-dichlorophenyl, 2,5-difluorophenyl, 2,5-dimethylphenyl,2,6-difluorophenyl, 2-bromophenyl, 2-chloro-5-nitrophenyl,2-chloro-6-fluorophenyl, 2-cyanophenyl, 2-ethylbutyryl, 2-fluorophenyl,2-(2-oxymethylenecarboxy)phenyl, 2-methoxy-1-naphthyl,2-nitro-5-chlorophenyl, 2-nitrophenyl, 2-pyridinyl,3,4-(methylenedioxy)-6-nitrophenyl, 3,4-difluorophenyl,3,5-bis(trifluoromethyl)phenyl, 3,5-dichlorophenyl,3-(3,4-dichlorophenoxy)phenyl, 3-bromo-4-fluorophenyl, 3-bromophenyl,3-carboxyphenyl, 3-cyanophenyl, 3-fluorophenyl, 3-chromonyl, 3-furyl,3-hydroxyphenyl, 3-nitro-4-chlorophenyl, 3-nitrophenyl, 3-phenoxyphenyl,2-phenylpropyl, 3-pyridinyl, 4-bromo-2-thiophene-yl, 4-bromophenyl,4-carboxyphenyl, 4-cyanophenyl, 4-fluorophenyl, 4-nitrophenyl,4-pyridinyl, 4-quinolinyl, 5-bromo-2-hydroxyphenyl, 5-nitro-2-furyl,5-norbornene-2-yl, 6-methyl-2-pyridinyl, 9-ethyl-3-carbazolyl,1,2-dimethylbutyryl, 1,1-dimethyl-3-butenyl, 3-methoxy-2-nitro-phenyl,3-hydroxy-4-nitrophenyl, 1-methylpropyl, 1-methylbutyl,4-chloro-3-nitrophenyl, 4-(trifluoromethyl)phenyl, 1-methyldecanyl, andβ-phenylcinnaminyl; R⁶ is selected from the group consisting ofnalidixoyl, 2-phenyl-4-quinolinecarboxy, 2-pyrazinecarboxy, niflumoyl,4-nitrophenylacetyl, 4-(4-nitrophenyl)butyroyl,(3,4-dimethoxyphenyl)-acetyl, 3,4-(methylenedioxy)phenylacetyl,4-nitrocinnamoyl, 3,4,-(methylenedioxy)cinnamoyl,3,4,5-trimethoxycinnamoyl, benzoyl, 2-chlorobenzoyl, 2-nitrobenzoyl,2-(p-toluoyl)benzoyl, 2,4-dinitrophenylacetyl,3-(3,4,5-trimethoxyphenyl)-propionyl, 4-biphenylacetyl, 1-napthylacetyl,(2-napthoxy)acetyl, trans-cinnamoyl, picolinyl,3-amino-4-hydroxybenzoyl, (4-pyridylthio)acetyl, 2,4-dichlorobenzoyl,3,4-dichlorobenzoyl, 4-biphenylcarboxy, thiophenoxyacetyl,1-benzoylpropionyl, phenylacetyl, hydrocinnamoyl, 3,3-diphenylpropionyl,3,3,3-triphenylpropionyl, 4-phenylbutyryl, phenoxyacetyl,(+/-)-2-phenoxypropionyl, 2,4-dimethoxybenzoyl, 3,4-dimethoxybenzoyl,3,4-dihydroxybenzoyl, 2,4-dihydroxybenzoyl, 3,4,5-trimethoxybenzoyl,3,4,5-triethoxybenzoyl, 3,4,5-trihydroxybenzoyl, 2-benzoylbenzoyl,1-napthoyl, xanthene-9-carboxy, 4-chloro-2-nitrobenzoyl,2-chloro-4-nitrobenzoyl, 4-chloro-3-nitrobenzoyl,2-chloro-5-nitrobenzoyl, 4-(dimethylamino)benzoyl,4-(diethylamino)benzoyl, 4-nitrobenzoyl, 3-(dimethylamino)benzoyl,p-methylbenzoyl, p-methoxybenzoyl, trimethylacetyl, tert-butylacetyl,(-)-menthoxyacetyl, cyclohexanecarboxy, cyclohexylacetyl,dicyclohexylacetyl, 4-cyclohexylbutyroyl, cycloheptanecarboxy,13-isopropylpodocarpa-7,13-dien-15-oyl, acetyl, octanoyl,(methylthio)acetyl, 3-nitropropionyl, 4-amino-3 hydroxybenzoyl,3-(2-methyl-4-nitro-1-imidizoyl)propionyl, 2-furoyl,(s)(-)-2-pyrrolidone-5-carboxy, (2-pyrimidylthio)acetyl,4-methoxy-2-quinolinecarboxy, 1-adamantanecarboxy, piperonoyl,5-methyl-3-phenylisoxazole-4-carboxy, rhodanine-3-acetyl,2-norbornaneacetyl, nicotinoyl, 9-oxo-9H-thioxanthene-3-carboxyl-10,10dioxide, 2-thiophenecarboxy, 5-nitro-2-furanoyl, indole-3-acetyl,isonicotinoyl, 3a-hydroxy-5β-cholan-24-oyl,(3α,7α,12α)-trihydroxy-5β-cholan-24-oyl, (3α, 5β-12α)-3,12,dihydroxy-5-cholan-24-oyl, (3α, 5β, 6α)-3,6-dihydroxy-cholan-24-oyl,L-alaninyl, L-cysteinyl, L-aspartinyl, L-glutaminyl, L-phenylalaninyl,glycinyl, L-histidinyl, L-isoleucinyl, L-lyscinyl, L-leucinyl,L-methionylsulfoxide, L-methionyl, L-asparginyl, L-prolinyl,L-glutaminyl, L-arganinyl, L-serinyl, L-threoninyl, L-valinyl,L-tryptophanoyl, L-tyrosinyl, D-alaninyl, D-cysteinyl, D-aspartinyl,D-glutaminyl, D-phenylalaninyl, glycinyl, D-histidinyl, D-isoleucinyl,D-lyscinyl, D-leucinyl, D-methionylsulfoxide, D-methionyl, D-asparginyl,D-prolinyl, D-glutaminyl, D-arganinyl, D-serinyl, D-threoninyl,D-valinyl, D-tryptophanoyl, tryptophanoyl, D-tyrosinyl, 2-aminobutyroyl,4-aminobutyroyl, 2-aminoisobutyroyl, L-norleucinyl, D-norleucinyl,6-aminohexanoyl, 7-aminoheptanoyl, thioprolinyl, L-norvalinyl,D-norvalinyl, a-ornithinyl, methionyl sulfonyl, L-naphthylalaninyl,D-naphthylalaninyl, L-phenylglycinyl, D-phenylglycinyl, D-alaninyl,L-cyclohexylalaninyl, D-cyclohexylalaninyl, hydroxyprolinyl,4-nitrophenylalaninyl, dehydroprolinyl, 3-hydroxy-1-propanesulfonyl,1-propanesulfonyl, 1-octanesulfonyl, perfluoro-1-octanesulfonly,(+)-10-camphorsulfonyl, (-)-10-camphorsulfonyl, benzenesulfonyl,2-nitrobenzenesulfonyl, p-toluenesulfonyl, 4-nitrobenzenesulfonyl,n-acetylsulfanilyl, 2,5-dichlorobenzenesulfonyl,2,4-dinitrobenzenesulfonyl, 2-mesitylenesulfonyl and2-napthalenesulfonyl; n is 1; and Y is C(O)NH₂.